572 results on '"Effector"'
Search Results
2. Chronic CD27-CD70 costimulation promotes type 1-specific polarization of effector Tregs
- Author
-
Hideo Yagita, Valérie Acolty, Muriel Moser, Oberdan Leo, Abdulkader Azouz, Stanislas Goriely, Natalia Bowakim Anta, and Guillaume Oldenhove
- Subjects
Physics ,History ,Polymers and Plastics ,Effector ,Immunology ,Immunology and Allergy ,Business and International Management ,Polarization (electrochemistry) ,Industrial and Manufacturing Engineering ,Cell biology ,CD70 - Abstract
IntroductionMost T lymphocytes, including regulatory T cells, express the CD27 costimulatory receptor in steady state conditions. There is evidence that CD27 engagement on conventional T lymphocytes favors the development of Th1 and cytotoxic responses in mice and humans, but the impact on the regulatory lineage is unknown.MethodsIn this report, we examined the effect of constitutive CD27 engagement on both regulatory and conventional CD4+ T cells in vivo, in the absence of intentional antigenic stimulation.ResultsOur data show that both T cell subsets polarize into type 1 Tconvs or Tregs, characterized by cell activation, cytokine production, response to IFN-γ and CXCR3-dependent migration to inflammatory sites. Transfer experiments suggest that CD27 engagement triggers Treg activation in a cell autonomous fashion.ConclusionWe conclude that CD27 may regulate the development of Th1 immunity in peripheral tissues as well as the subsequent switch of the effector response into long-term memory.
- Published
- 2023
3. Functional characterization of VirB/VirD4 and Icm/Dot type IV secretion systems from the plant-pathogenic bacterium Xanthomonas euvesicatoria .
- Author
-
Drehkopf S, Scheibner F, and Büttner D
- Subjects
- Animals, Humans, Type IV Secretion Systems genetics, Eukaryota, Xanthomonas genetics, Legionella pneumophila
- Abstract
Introduction: Many Gram-negative plant- and animal-pathogenic bacteria employ type IV secretion (T4S) systems to transport proteins or DNA/protein complexes into eukaryotic or bacterial target cells. T4S systems have been divided into minimized and expanded T4S systems and resemble the VirB/VirD4 T4S system from the plant pathogen Agrobacterium tumefaciens and the Icm/Dot T4S system from the human pathogen Legionella pneumophila , respectively. The only known plant pathogen with both types of T4S systems is Xanthomonas euvesicatoria which is the causal agent of bacterial spot disease on pepper and tomato plants., Results and Discussion: In the present study, we show that virB/virD4 and icm/dot T4S genes are expressed and encode components of oligomeric complexes corresponding to known assemblies of VirB/VirD4 and Icm/Dot proteins. Both T4S systems are dispensable for the interaction of X. euvesicatoria with its host plants and do not seem to confer contact-dependent lysis of other bacteria, which was previously shown for the chromosomally encoded VirB/VirD4 T4S system from Xanthomonas axonopodis pv. citri. The corresponding chromosomal T4S gene cluster from X. euvesicatoria is incomplete, however, the second plasmid-localized vir gene cluster encodes a functional VirB/VirD4 T4S system which contributes to plasmid transfer. In agreement with this finding, we identified the predicted relaxase TraI as substrate of the T4S systems from X. euvesicatoria . TraI and additional candidate T4S substrates with homology to T4S effectors from X. axonopodis pv. citri interact with the T4S coupling protein VirD4. Interestingly, however, the predicted C-terminal VirD4-binding sites are not sufficient for T4S, suggesting the contribution of additional yet unknown mechanisms to the targeting of T4S substrates from X. euvesicatoria to both VirB/VirD4 and Icm/Dot T4S systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Drehkopf, Scheibner and Büttner.)
- Published
- 2023
- Full Text
- View/download PDF
4. Editorial: Population and comparative genomics of plant pathogenic bacteria
- Author
-
Sujan, Timilsina, Erica M, Goss, Ralf, Koebnik, Neha, Potnis, Jeffrey B, Jones, University of Florida [Gainesville] (UF), Plant Health Institute of Montpellier (UMR PHIM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), and Auburn University (AU)
- Subjects
Microbiology (medical) ,taxonomy ,evolution ,Effector ,host specificity ,ecology ,Microbiology ,[SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy - Abstract
International audience; Plant pathogenic bacteria are among the major challenges in crop production, amplified by their continuous and rapid evolution and resulting in the emergence of virulent, competitive, and elusive plant pathogens. To further understand these bacteria, their interactions with host plants, and their responses to disease management, comprehensive methods are necessary. In recent years, phytobacteriology research has used population and comparative studies to quantify the diversity of plant pathogenic bacteria and their virulence mechanisms, including the effectors secreted from different protein secretion systems, phytohormones, or toxins that mediate their interactions with the hosts and/or competing microbes in the phyllosphere. Studies comparing strains over time, within and among geographic regions, and across phylogenetic trees has provided insights into scales of variation and changes in pathogens over time and in response to selection pressures. In this series of articles, population and comparative genomics were used to investigate plant pathogens representing diverse bacterial genera including Gram-negative bacteria composed of facultative anaerobes (i.e., Dickeya, Pantoea, and Pectobacterium) as well as obligate aerobes (i.e., Pseudomonas, Xanthomonas, and Xylella) as well as the Gram-positive genus, Clavibacter.
- Published
- 2022
5. Randomized, Double-Blind, Reference-Controlled, Phase 2a Study Evaluating the Immunogenicity and Safety of OVX836, A Nucleoprotein-Based Influenza Vaccine
- Author
-
Isabel Leroux-Roels, Gwenn Waerlop, Jessika Tourneur, Fien De Boever, Catherine Maes, Jacques Bruhwyler, Delphine Guyon-Gellin, Philippe Moris, Judith Del Campo, Paul Willems, Geert Leroux-Roels, Alexandre Le Vert, and Florence Nicolas
- Subjects
Adult ,safety ,Adolescent ,Immunology ,EFFECTOR ,immunogenicity ,Interferon-gamma ,Young Adult ,Double-Blind Method ,Influenza, Human ,universal vaccine ,Medicine and Health Sciences ,Humans ,Immunology and Allergy ,Vaccines, Combined ,subunit ,Influvac ,Aged ,nucleoprotein ,Vaccines, Synthetic ,virus diseases ,Middle Aged ,Nucleoproteins ,Influenza Vaccines ,Tetra ,Immunoglobulin G ,CELLS ,OVX836 ,influenza - Abstract
OVX836 is a recombinant protein-based vaccine targeting the highly conserved influenza nucleoprotein (NP), which aims to confer a broad-spectrum protection against influenza. In a Phase 1 study, OVX836, administered intramuscularly, has been found safe and immunogenic. The 90µg and 180µg dose levels were selected to be further evaluated in this randomized, monocenter, reference-controlled (Influvac Tetra™: quadrivalent seasonal influenza subunit vaccine), parallel group, double-blind, Phase 2a study in 300 healthy volunteers, aged 18-65 years, during the 2019/2020 flu season. Safety, influenza-like illness episodes (ILI; based on the Flu-PRO® questionnaire) and immunogenicity were assessed up to 180 days post-vaccination. OVX836 was safe and presented a reactogenicity profile similar to Influvac Tetra. It induced a significant increase in terms of NP-specific interferon-gamma (IFNγ) spot forming cells (SFCs), NP-specific CD4+ T-cells (essentially polyfunctional cells) and anti-NP IgG responses. OVX836 was superior to Influvac Tetra for all immunological parameters related to NP, and the 180µg dose was significantly superior to the 90µg dose for SFCs and CD4+ T-cells expressing IFNγ. Both the CD4+ T-cell and the anti-NP IgG responses persisted up to Day 180. An efficacy signal was observed with OVX836 at 180µg through reduction of ILI episodes occurring during the flu season as of 14 days post-vaccination. In conclusion, these results encourage further clinical evaluation of OVX836 in order to confirm the signal of efficacy on ILIs and/or laboratory-confirmed influenza cases. NCT04192500 (https://clinicaltrials.gov/ct2/show/study/NCT04192500)
- Published
- 2022
- Full Text
- View/download PDF
6. Identification of Type VI Secretion Systems Effector Proteins That Contribute to Interbacterial Competition in Salmonella Dublin
- Author
-
Fernando A. Amaya, Carlos J. Blondel, María F. Barros-Infante, Dácil Rivera, Andrea I. Moreno-Switt, Carlos A. Santiviago, and David Pezoa
- Subjects
Microbiology (medical) ,T6SS ,effector ,animal diseases ,interbacterial competition ,bacteria ,immunity protein ,biochemical phenomena, metabolism, and nutrition ,Microbiology ,QR1-502 ,Salmonella Dublin - Abstract
The Type VI Secretion System (T6SS) is a multiprotein device that has emerged as an important fitness and virulence factor for many Gram-negative bacteria through the injection of effector proteins into prokaryotic or eukaryotic cells via a contractile mechanism. While some effector proteins specifically target bacterial or eukaryotic cells, others can target both types of cells (trans-kingdom effectors). In Salmonella, five T6SS gene clusters have been identified within pathogenicity islands SPI-6, SPI-19, SPI-20, SPI-21, and SPI-22, which are differentially distributed among serotypes. Salmonella enterica serotype Dublin (S. Dublin) is a cattle-adapted pathogen that harbors both T6SSSPI-6 and T6SSSPI-19. Interestingly, while both systems have been linked to virulence and host colonization in S. Dublin, an antibacterial activity has not been detected for T6SSSPI-6 in this serotype. In addition, there is limited information regarding the repertoire of effector proteins encoded within T6SSSPI-6 and T6SSSPI-19 gene clusters in S. Dublin. In the present study, we demonstrate that T6SSSPI-6 and T6SSSPI-19 of S. Dublin CT_02021853 contribute to interbacterial competition. Bioinformatic and comparative genomic analyses allowed us to identify genes encoding three candidate antibacterial effectors located within SPI-6 and two candidate effectors located within SPI-19. Each antibacterial effector gene is located upstream of a gene encoding a hypothetic immunity protein, thus conforming an effector/immunity (E/I) module. Of note, the genes encoding these effectors and immunity proteins are widely distributed in Salmonella genomes, suggesting a relevant role in interbacterial competition and virulence. Finally, we demonstrate that E/I modules SED_RS01930/SED_RS01935 (encoded in SPI-6), SED_RS06235/SED_RS06230, and SED_RS06335/SED_RS06340 (both encoded in SPI-19) contribute to interbacterial competition in S. Dublin CT_02021853.
- Published
- 2022
7. Transcriptome Profiling of Porcine Naïve, Intermediate and Terminally Differentiated CD8+ T Cells
- Author
-
Lagumdzic, Emil, Mair, Kerstin H., Saalmüller, Armin, Schmitt, Michael W., Olgiati, Simone, Pernold, Clara, and Viano, Marta
- Subjects
Mice ,Swine ,T-Lymphocyte Subsets ,Gene Expression Profiling ,Ionomycin ,Immunology ,Cytotoxic-T ,Effector ,Memory ,Expression ,Receptor ,Subsets ,Virus ,Lymphocytes ,Infection ,Responses ,Immunology and Allergy ,Animals ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation - Abstract
The pig has the potential to become a leading research model for human diseases, pharmacological and transplantation studies. Since there are many similarities between humans and pigs, especially concerning anatomy, physiology and metabolism, there is necessity for a better understanding of the porcine immune system. In adaptive immunity, cytotoxic T lymphocytes (CTLs) are essential for host defense. However, most data on CTLs come from studies in mice, non-human primates and humans, while detailed information about porcine CD8+ CTLs is still sparse. Aim of this study was to analyze transcriptomes of three subsets of porcine CD8β+ T-cell subsets by using next-generation sequencing technology. Specifically, we described transcriptional profiles of subsets defined by their CD11a/CD27 expression pattern, postulated as naïve (CD8β+CD27+CD11alow), intermediate differentiated (CD8β+CD27dimCD11a+), and terminally differentiated cells (CD8β+CD27-CD11ahigh). Cells were analyzed in ex vivo condition as well as upon in vitro stimulation with concanavalin A (ConA) and PMA/ionomycin. Our analyses show that the highest number of differentially expressed genes was identified between naïve and terminally differentiated CD8+ T-cell subsets, underlining their difference in gene expression signature and respective differentiation stages. Moreover, genes related to early (IL7-R, CCR7, SELL, TCF7, LEF1, BACH2, SATB1, ZEB1 and BCL2) and late (KLRG1, TBX21, PRDM1, CX3CR1, ZEB2, ZNF683, BATF, EZH2 and ID2) stages of CD8+ T-cell differentiation were highly expressed in the naïve and terminally differentiated CD8+ T-cell subsets, respectively. Intermediate differentiated CD8+ T-cell subsets shared a more comparable gene expression profile associated with later stages of T-cell differentiation. Genes associated with cytolytic activity (GNLY, PRF1, GZMB, FASL, IFNG and TNF) were highly expressed in terminally and intermediate differentiated CD8+ T-cell subsets, while naïve CD8+ T cells lacked expression even after in vitro stimulation. Overall, PMA/ionomycin stimulation induced much stronger upregulation of genes compared to stimulation with ConA. Taken together, we provided comprehensive results showing transcriptional profiles of three differentiation stages of porcine CD8+ T-cell subsets. In addition, our study provides a powerful toolbox for the identification of candidate markers to characterize porcine immune cell subsets in more detail.
- Published
- 2022
8. Type 1 secretion system and effectors in Rickettsiales.
- Author
-
Bui DC, Luo T, and McBride JW
- Subjects
- Humans, Animals, Bacterial Proteins metabolism, Type IV Secretion Systems, Ehrlichia, Host-Pathogen Interactions, Type I Secretion Systems, Rickettsiales metabolism
- Abstract
Obligate intracellular bacteria in the order Rickettsiales are transmitted by arthropod vectors and cause life-threatening infections in humans and animals. While both type 1 and type 4 secretion systems (T1SS and T4SS) have been identified in this group, the most extensive studies of Rickettsiales T1SS and associated effectors have been performed in Ehrlichia . These studies have uncovered important roles for the T1SS effectors in pathobiology and immunity. To evade innate immune responses and promote intracellular survival, Ehrlichia and other related obligate pathogens secrete multiple T1SS effectors which interact with a diverse network of host targets associated with essential cellular processes. T1SS effectors have multiple functional activities during infection including acting as nucleomodulins and ligand mimetics that activate evolutionarily conserved cellular signaling pathways. In Ehrlichia , an array of newly defined major immunoreactive proteins have been identified that are predicted as T1SS substrates and have conformation-dependent antibody epitopes. These findings highlight the underappreciated and largely uncharacterized roles of T1SS effector proteins in pathobiology and immunity. This review summarizes current knowledge regarding roles of T1SS effectors in Rickettsiales members during infection and explores newly identified immunoreactive proteins as potential T1SS substrates and targets of a protective host immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bui, Luo and McBride.)
- Published
- 2023
- Full Text
- View/download PDF
9. Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila
- Author
-
Jingjing, Luo, Lidong, Wang, Lei, Song, and Zhao-Qing, Luo
- Subjects
virulence ,Microbiology (medical) ,effector ,ubiquitin ,intracellular pathogen ,Review ,immunity ,Microbiology ,QR1-502 - Abstract
Ubiquitination is a commonly used post-translational modification (PTM) in eukaryotic cells, which regulates a wide variety of cellular processes, such as differentiation, apoptosis, cell cycle, and immunity. Because of its essential role in immunity, the ubiquitin network is a common target of infectious agents, which have evolved various effective strategies to hijack and co-opt ubiquitin signaling for their benefit. The intracellular pathogen Legionella pneumophila represents one such example; it utilizes a large cohort of virulence factors called effectors to modulate diverse cellular processes, resulting in the formation a compartment called the Legionella-containing vacuole (LCV) that supports its replication. Many of these effectors function to re-orchestrate ubiquitin signaling with distinct biochemical activities. In this review, we highlight recent progress in the mechanism of action of L. pneumophila effectors involved in ubiquitination and discuss their roles in bacterial virulence and host cell biology.
- Published
- 2021
10. Oncolytic Virotherapy: From Bench to Bedside
- Author
-
Ludi Yang, Xiang Gu, Jie Yu, Shengfang Ge, and Xianqun Fan
- Subjects
tumor ,mechanisms ,QH301-705.5 ,Genetically modified virus ,business.industry ,Effector ,medicine.medical_treatment ,Cancer ,Review ,Cell Biology ,Immunotherapy ,clinical applications ,medicine.disease ,immunity ,Oncolytic virus ,Radiation therapy ,Cell and Developmental Biology ,Immune system ,Immunity ,Cancer research ,Medicine ,Biology (General) ,business ,oncolytic virus ,Developmental Biology - Abstract
Oncolytic viruses are naturally occurring or genetically engineered viruses that can replicate preferentially in tumor cells and inhibit tumor growth. These viruses have been considered an effective anticancer strategy in recent years. They mainly function by direct oncolysis, inducing an anticancer immune response and expressing exogenous effector genes. Their multifunctional characteristics indicate good application prospects as cancer therapeutics, especially in combination with other therapies, such as radiotherapy, chemotherapy and immunotherapy. Therefore, it is necessary to comprehensively understand the utility of oncolytic viruses in cancer therapeutics. Here, we review the characteristics, antitumor mechanisms, clinical applications, deficiencies and associated solutions, and future prospects of oncolytic viruses.
- Published
- 2021
11. The Roles of Gasdermin D in Coronavirus Infection and Evasion
- Author
-
Pinghuang Liu, Xiang Liu, and Shihao Ding
- Subjects
Microbiology (medical) ,Programmed cell death ,Innate immune system ,biology ,Effector ,gasdermin D ,pyroptosis ,coronaviruses ,Pyroptosis ,Review ,medicine.disease_cause ,Microbiology ,QR1-502 ,Virus ,Cell biology ,Lytic cycle ,biology.protein ,medicine ,viruses ,inflammasomes ,Caspase ,Coronavirus - Abstract
Pyroptosis is lytic, programmed cell death and plays a critical role against microbial invasion, functioning as an innate immune effector mechanism. The pore-forming protein gasdermin D (GSDMD), a member of gasdermin family proteins, is a primary effector of pyroptosis. The cleavage of inflammasome-associated inflammatory caspases activates GSDMD to liberate the N-terminal effector domain from the C-terminal inhibitory domain and form pores in the cellular plasma membrane. Emerging evidence shows that the pore-forming activity of GSDMD beyond pyroptosis and modifies non-lytic cytosolic protein secretion in living cells and innate immunity. While the essential roles of GSDMD in bacterial infection and cancer have been widely investigated, the importance of GSDMD in virus infection, including coronaviruses, remains elusive. Here, we review the current literature regarding the activation and functions of GSDMD during virus infections. Last, we further discuss the roles of GSDMD and the therapeutic potential of targeting this GSDMD pore-forming activity in coronavirus diseases.
- Published
- 2021
12. EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
- Author
-
Haikuo Zhang, Shahram Salek-Ardakani, Catherine Lee, Wenjing Yang, Christopher P. Dillon, Sophia Pfister, Eleanore Hendrickson, Christopher J. Stairiker, Tao Xie, and Graham D. Thomas
- Subjects
Agonist ,Cell Survival ,medicine.drug_class ,CD137 (4-1BB) ,T cell ,Immunology ,CD8-Positive T-Lymphocytes ,Biology ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Enhancer of Zeste Homolog 2 Protein ,Bim ,EZH2 ,Enzyme Inhibitors ,Receptor ,Original Research ,Mice, Inbred BALB C ,Effector ,Antibodies, Monoclonal ,Neoplasms, Experimental ,CD8 ,RC581-607 ,Immune checkpoint ,Tumor Burden ,Blockade ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Gene Expression Regulation ,Cancer research ,Immunologic diseases. Allergy - Abstract
Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB). Our data show that EZH2i compromise the efficacy of α4-1BB in both CT26 colon carcinoma and in an in vivo protein immunization model. We link this to reduced effector survival and increased BIM expression in CD8+ T cells upon EZH2i treatment. These data support the requirement of EZH2 function in 4-1BB-mediated CD8+ T cell expansion and effector programming and emphasize the consideration that must be given when combining such antitumoral therapies.
- Published
- 2021
13. Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
- Author
-
Marlies J. W. Peeters, Pia Aehnlich, Adriano Pizzella, Kasper Mølgaard, Tina Seremet, Özcan Met, Lene Juel Rasmussen, Per thor Straten, and Claus Desler
- Subjects
biology ,Effector ,Chemistry ,T cell ,CD3 ,Immunology ,T-cell metabolism ,Oxidative phosphorylation ,RC581-607 ,Acquired immune system ,pyrimidine de novo synthesis ,mitochondrial respiration and oxidative respiration ,Cell biology ,medicine.anatomical_structure ,T-cell activation ,Pyrimidine metabolism ,medicine ,biology.protein ,Dihydroorotate dehydrogenase ,immunosenescence and exhaustion ,Immunology and Allergy ,Immunologic diseases. Allergy ,Intracellular - Abstract
T-cell activation upon antigen stimulation is essential for the continuation of the adaptive immune response. Impairment of mitochondrial oxidative phosphorylation is a well-known disruptor of T-cell activation. Dihydroorotate dehydrogenase (DHODH) is a component of the de novo synthesis of pyrimidines, the activity of which depends on functional oxidative phosphorylation. Under circumstances of an inhibited oxidative phosphorylation, DHODH becomes rate-limiting. Inhibition of DHODH is known to block clonal expansion and expression of effector molecules of activated T cells. However, this effect has been suggested to be caused by downstream impairment of oxidative phosphorylation rather than a lower rate of pyrimidine synthesis. In this study, we successfully inhibit the DHODH of T cells with no residual effect on oxidative phosphorylation and demonstrate a dose-dependent inhibition of proliferation of activated CD3+ T cells. This block is fully rescued when uridine is supplemented. Inhibition of DHODH does not alter expression of effector molecules but results in decreased intracellular levels of deoxypyrimidines without decreasing cell viability. Our results clearly demonstrate the DHODH and mitochondrial linked pyrimidine synthesis as an independent and important cytostatic regulator of activated T cells.
- Published
- 2021
14. Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy
- Author
-
Myeong Joon Kim and Sang-Jun Ha
- Subjects
QH301-705.5 ,animal diseases ,medicine.medical_treatment ,Review ,functional restoration ,Cell and Developmental Biology ,Immune system ,Cancer immunotherapy ,tumor microenvironment ,Medicine ,Biology (General) ,Receptor ,Tumor microenvironment ,cancer immunotherapy ,business.industry ,Effector ,Cancer ,Cell Biology ,medicine.disease ,Immune checkpoint ,programmed cell death protein 1 (PD-1) ,Cancer research ,business ,tumor-infiltrating effector cells ,CD8 ,tumor-infiltrating suppressive cells ,Developmental Biology - Abstract
In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8+ T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8+ T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8+ T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.
- Published
- 2021
15. JAZ8 Interacts With VirE3 Attenuating Agrobacterium Mediated Root Tumorigenesis
- Author
-
Bingliang Xu, Paul J. J. Hooykaas, Xiaolei Niu, Shijuan Li, Xiang Lu, Meiliang Zhou, and Jianping Cheng
- Subjects
Arabidopsis thaliana ,Agrobacterium ,Virulence ,Plant Science ,SB1-1110 ,Bimolecular fluorescence complementation ,Virulence Factor ,Arabidopsis ,Plant Immunity ,Effector Protein ,Original Research ,biology ,Effector ,fungi ,Plant culture ,Agrobacterium tumefaciens ,JAZ8 ,biology.organism_classification ,Cell biology ,Signal transduction ,Crown Gall Tumor Formation ,jasmonates ,VirE3 - Abstract
Agrobacterium tumefaciens can cause crown gall tumors by transferring both an oncogenic piece of DNA (T-DNA) and several effector proteins into a wide range of host plants. For the translocated effector VirE3 multiple functions have been reported. It acts as a transcription factor in the nucleus binding to the Arabidopsis thaliana pBrp TFIIB-like protein to activate the expression of VBF, an F-box protein involved in degradation of the VirE2 and VIP1 proteins, facilitating Agrobacterium-mediated transformation. Also VirE3 has been found at the plasma membrane, where it could interact with VirE2. Here, we identified AtJAZ8 in a yeast two-hybrid screening with VirE3 as a bait and confirmed the interaction by pull-down and bimolecular fluorescence complementation assays. We also found that the deletion of virE3 reduced Agrobacterium virulence in a root tumor assay. Overexpression of virE3 in Arabidopsis enhanced tumorigenesis, whereas overexpression of AtJAZ8 in Arabidopsis significantly decreased the numbers of tumors formed. Further experiments demonstrated that AtJAZ8 inhibited the activity of VirE3 as a plant transcriptional regulator, and overexpression of AtJAZ8 in Arabidopsis activated AtPR1 gene expression while it repressed the expression of AtPDF1.2. Conversely, overexpression of virE3 in Arabidopsis suppressed the expression of AtPR1 whereas activated the expression of AtPDF1.2. Our results proposed a novel mechanism of counter defense signaling pathways used by Agrobacterium, suggesting that VirE3 and JAZ8 may antagonistically modulate the salicylic acid/jasmonic acid (SA/JA)-mediated plant defense signaling response during Agrobacterium infection.
- Published
- 2021
- Full Text
- View/download PDF
16. Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors
- Author
-
Musiliu A. Oyenike, Ibrahim Bello, T. Oduola, Abdurrasheed Ola Ola Muhammed, Sikiru O. Imodoye, Kamoru A. Adedokun, and M. A. Muhibi
- Subjects
Cancer Research ,tumour ,Effector ,EMT ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,ontogenesis ,Review ,Biology ,medicine.disease ,microenvironment ,Metastasis ,Oncology ,Downregulation and upregulation ,transcription factors ,Cancer research ,medicine ,metastasis ,embryogenesis ,Epithelial–mesenchymal transition ,Wound healing ,Psychological repression ,Transcription factor ,RC254-282 - Abstract
Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs via a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but also resistant to several cytotoxic agents during treatment, owing to their anatomically diffuse localisation in the body system. As the quest to find an effective method of addressing metastasis in cancer intervention heightens, understanding the molecular interplay involving the signalling pathways, downstream effectors, and their interactions with the EMT would be an important requisite while the challenges of metastasis continue to punctuate. Unfortunately, the molecular underpinnings that govern this process remain to be completely illuminated. However, it is becoming increasingly clear that EMT, which initiates every episode of metastasis, significantly requires some master regulators called EMT transcription factors (EMT-TFs). Thus, this review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation. In addition, it discusses the interaction of various signalling molecules and effector proteins with these factors. It also provides insight into promising therapeutic targets that may inhibit the metastatic process to overcome the limitation of “undruggable” cancer targets in therapeutic design and upturn the current spate of drug resistance. More so, it extends the discussion from the basic understanding of the EMT binary switch model, and ultimately unveiling the E/M cellular plasticity along a phenotypic spectrum via multiple trans-differentiations. It wraps up on how this knowledge update shapes the diagnostic and clinical approaches that may demand a potential shift in investigative paradigm using novel technologies such as single-cell analyses to improve overall patient survival.
- Published
- 2021
17. Corrigendum: Bioinformatic Analysis of the Campylobacter jejuni Type VI Secretion System and Effector Prediction
- Author
-
Luca Robinson, Janie Liaw, Zahra Omole, Dong Xia, Arnoud H. M. van Vliet, Nicolae Corcionivoschi, Abderrahman Hachani, and Ozan Gundogdu
- Subjects
Microbiology (medical) ,Type VI Secretion System ,Effector ,Biology ,biology.organism_classification ,Pathogenicity island ,Campylobacter jejuni ,Microbiology ,toxin-antitoxin ,QR1-502 ,pathogenicity island ,T6SS effectors ,T6SS immunity proteins ,Type VI secretion system - Abstract
[This corrects the article DOI: 10.3389/fmicb.2021.694824.].
- Published
- 2021
18. Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators
- Author
-
Javier Perez-Hernandez, Valerio Chiurchiù, Sylvain Perruche, and Sylvaine You
- Subjects
chronic inflammation ,T cell ,T-Lymphocytes ,Immunology ,Inflammation ,Review ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Autoimmunity ,03 medical and health sciences ,Immunomodulating Agents ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Immunology and Allergy ,030304 developmental biology ,0303 health sciences ,therapy ,Effector ,autoimmunity ,resolution ,Lipid signaling ,adaptive immunity ,RC581-607 ,Acquired immune system ,Cellular Reprogramming ,3. Good health ,Lipoxins ,medicine.anatomical_structure ,Eicosapentaenoic Acid ,specialized pro-resolving lipid mediators (SPMs) ,Eicosanoids ,medicine.symptom ,Immunologic diseases. Allergy ,Inflammation Mediators ,Homeostasis ,030215 immunology - Abstract
Both the initiation and the resolution of inflammatory responses are governed by the sequential activation, migration, and control/suppression of immune cells at the site of injury. Bioactive lipids play a major role in the fine-tuning of this dynamic process in a timely manner. During inflammation and its resolution, polymorphonuclear cells (PMNs) and macrophages switch from producing pro-inflammatory prostaglandins and leukotrienes to specialized pro-resolving lipid mediators (SPMs), namely, lipoxins, resolvins, protectins, and maresins, which are operative at the local level to limit further inflammation and tissue injury and restore homeostasis. Accumulating evidences expand now the role and actions of these lipid mediators from innate to adaptive immunity. In particular, SPMs have been shown to contribute to the control of chronic inflammation, and alterations in their production and/or function have been associated with the persistence of several pathological conditions, including autoimmunity, in human and experimental models. In this review, we focus on the impact of pro-resolving lipids on T cells through their ability to modulate T-cell responses. In particular, the effects of the different families of SPMs to restrain effector T-cell functions while promoting regulatory T cells will be reviewed, along with the underlying mechanisms. Furthermore, the emerging concept of SPMs as new biological markers for disease diagnostic and progression and as putative therapeutic tools to regulate the development and magnitude of inflammatory and autoimmune diseases is discussed.
- Published
- 2021
- Full Text
- View/download PDF
19. Involvement of the Heat Shock Protein HtpG of Salmonella Typhimurium in Infection and Proliferation in Hosts
- Author
-
Tao Dong, Weiwei Wang, Minhao Xia, Shujie Liang, Guangzhong Hu, Hui Ye, Qingyun Cao, Zemin Dong, Changming Zhang, Dingyuan Feng, and Jianjun Zuo
- Subjects
Salmonella typhimurium ,Microbiology (medical) ,Salmonella ,Immunology ,Biology ,medicine.disease_cause ,Microbiology ,Cellular and Infection Microbiology ,Bacterial Proteins ,Immunity ,Heat shock protein ,medicine ,Animals ,Humans ,Pathogen ,Heat-Shock Proteins ,Original Research ,Cell Proliferation ,Effector ,Biofilm ,Chemotaxis ,biology.organism_classification ,immunity ,QR1-502 ,infection ,Infectious Diseases ,bacteria ,HtpG ,RNA-seq ,Bacteria - Abstract
Salmonella Typhimurium is a common pathogen infecting the gastrointestinal tract of humans and animals, causing host gastroenteritis and typhoid fever. Heat shock protein (HtpG) as a molecular chaperone is involved in the various cellular processes of bacteria, especially under environmental stress. However, the potential association of HtpG with S. Typhimurium infection remains unknown. In this study, we clarified that HtpG could also play a role as an effector in S. Typhimurium infection. RNA-seq indicated that the flagellar assembly pathway, infection pathway, and chemotaxis pathway genes of S. Typhimurium were downregulated after the mutation of HtpG, which resulted in compromises of S. Typhimurium motility, biofilm formation, adhesion, invasion, and inflammation-inducing ability. In addition, HtpG recombinant protein was capable of promoting the proliferation of S. Typhimurium in host cells and the resultant inflammation. Collectively, our results illustrated an important role of HtpG in S. Typhimurium infection.
- Published
- 2021
20. Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1
- Author
-
Jie Liu, Zhen-Ni Guo, Xiu-Li Yan, Yi Yang, and Shuo Huang
- Subjects
Aging ,treatment ,Effector ,Mechanism (biology) ,business.industry ,Cognitive Neuroscience ,Alternative splicing ,Central nervous system ,Aging Neuroscience ,mechanism ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Review ,central nervous system ,Bioinformatics ,medicine.disease ,Myotonic dystrophy ,Pathogenesis ,Gene product ,medicine.anatomical_structure ,medicine ,pathology ,Muscular dystrophy ,business ,myotonic dystrophy type 1 ,RC321-571 - Abstract
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy that affects multiple systems including the muscle and heart. The mutant CTG expansion at the 3′-UTR of the DMPK gene causes the expression of toxic RNA that aggregate as nuclear foci. The foci then interfere with RNA-binding proteins, affecting hundreds of mis-spliced effector genes, leading to aberrant alternative splicing and loss of effector gene product functions, ultimately resulting in systemic disorders. In recent years, increasing clinical, imaging, and pathological evidence have indicated that DM1, though to a lesser extent, could also be recognized as true brain diseases, with more and more researchers dedicating to develop novel therapeutic tools dealing with it. In this review, we summarize the current advances in the pathogenesis and pathology of central nervous system (CNS) deficits in DM1, intervention measures currently being investigated are also highlighted, aiming to promote novel and cutting-edge therapeutic investigations.
- Published
- 2021
21. Construction of sRNA Regulatory Network for Magnaporthe oryzae Infecting Rice Based on Multi-Omics Data
- Author
-
Enshuang Zhao, Hao Zhang, Xueqing Li, Tianheng Zhao, and Hengyi Zhao
- Subjects
Effector ,Mechanism (biology) ,rice ,food and beverages ,Magnaporthe oryzae ,Computational biology ,multi-omics ,QH426-470 ,Biology ,Proteomics ,Transcriptome ,machine learning ,Secretory protein ,RNA interference ,Transfer RNA ,Genetics ,Molecular Medicine ,sRNA ,protein ,Genetics (clinical) - Abstract
Studies have shown that fungi cause plant diseases through cross-species RNA interference mechanism (RNAi) and secreted protein infection mechanism. The small RNAs (sRNAs) of Magnaporthe oryzae use the RNAi mechanism of rice to realize the infection process, and different effector proteins can increase the autotoxicity by inhibiting pathogen-associated molecular patterns triggered immunity (PTI) to achieve the purpose of infection. However, the coordination of sRNAs and proteins in the process of M. oryzae infecting rice is still poorly understood. Therefore, the combination of transcriptomics and proteomics to study the mechanism of M. oryzae infecting rice has important theoretical significance and practical value for controlling rice diseases and improving rice yields. In this paper, we used the high-throughput data of various omics before and after the M. oryzae infecting rice to screen differentially expressed genes and sRNAs and predict protein interaction pairs based on the interolog and the domain-domain methods. We were then used to construct a prediction model of the M. oryzae-rice interaction proteins according to the obtained proteins in the proteomic network. Finally, for the differentially expressed genes, differentially expressed sRNAs, the corresponding mRNAs of rice and M. oryzae, and the interacting protein molecules, the M. oryzae-rice sRNA regulatory network was built and analyzed, the core nodes were selected. The functional enrichment analysis was conducted to explore the potential effect pathways and the critical infection factors of M. oryzae sRNAs and proteins were mined and analyzed. The results showed that 22 sRNAs of M. oryzae, 77 secretory proteins of M. oryzae were used as effect factors to participate in the infection process of M. oryzae. And many significantly enriched GO modules were discovered, which were related to the infection mechanism of M. oryzae.
- Published
- 2021
22. Distinct CD4−CD8− (Double-Negative) Memory T-Cell Subpopulations Are Associated With Indeterminate and Cardiac Clinical Forms of Chagas Disease
- Author
-
Livia Silva Araújo Passos, Carolina Cattoni Koh, Luísa Mourão Dias Magalhães, Maria do Carmo Pereira Nunes, Kenneth John Gollob, and Walderez Ornelas Dutra
- Subjects
Adult ,Chagas Cardiomyopathy ,Male ,Chagas disease ,Heart disease ,immunoregulation ,Trypanosoma cruzi ,CD8 Antigens ,Immunology ,Cardiomyopathy ,Double negative ,Inflammation ,Ventricular Function, Left ,Electrocardiography ,Memory T Cells ,Chlorocebus aethiops ,memory response ,medicine ,Animals ,Humans ,Immunology and Allergy ,Vero Cells ,Cells, Cultured ,Original Research ,Aged ,business.industry ,Effector ,RC581-607 ,Middle Aged ,medicine.disease ,Interleukin-10 ,double-negative T cells ,medicine.anatomical_structure ,CD4 Antigens ,pathology ,Female ,Immunologic diseases. Allergy ,Antigens, CD1d ,medicine.symptom ,business ,cardiomyopathy ,Memory T cell ,CD8 - Abstract
CD4−CD8− (double-negative, DN) T cells are critical orchestrators of the cytokine network associated with the pathogenic inflammatory response in one of the deadliest cardiomyopathies known, Chagas heart disease, which is caused by Trypanosoma cruzi infection. Here, studying the distribution, activation status, and cytokine expression of memory DN T-cell subpopulations in Chagas disease patients without cardiac involvement (indeterminate form—IND) or with Chagas cardiomyopathy (CARD), we report that while IND patients displayed a higher frequency of central memory, CARD had a high frequency of effector memory DN T cells. In addition, central memory DN T cells from IND displayed a balanced cytokine profile, characterized by the concomitant expression of IFN-γ and IL-10, which was not observed in effector memory DN T cells from CARD. Supporting potential clinical relevance, we found that the frequency of central memory DN T cells was associated with indicators of better ventricular function, while the frequency of effector memory DN T cells was not. Importantly, decreasing CD1d-mediated activation of DN T cells led to an increase in IL-10 expression by effector memory DN T cells from CARD, restoring a balanced profile similar to that observed in the protective central memory DN T cells. Targeting the activation of effector memory DN T cells may emerge as a strategy to control inflammation in Chagas cardiomyopathy and potentially in other inflammatory diseases where these cells play a key role.
- Published
- 2021
23. Continuous Modeling of T CD4 Lymphocyte Activation and Function
- Author
-
David Martínez-Méndez, Luis Mendoza, Carlos Villarreal, and Leonor Huerta
- Subjects
CD4-Positive T-Lymphocytes ,T cell ,T CD4 cells ,Immunology ,Lymphocyte Activation ,Oxidative Phosphorylation ,regulatory network ,medicine ,Animals ,Humans ,Immunology and Allergy ,Protein kinase A ,Antigen-presenting cell ,PI3K/AKT/mTOR pathway ,Original Research ,Effector ,Chemistry ,Models, Immunological ,AMPK ,CD28 ,Cell Differentiation ,RC581-607 ,Models, Theoretical ,Acquired immune system ,Cell biology ,medicine.anatomical_structure ,mTOR ,CTLA-4 ,Immunologic diseases. Allergy ,T cell receptor ,metabolism ,mathematical model - Abstract
T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes. The regulation of cell metabolism is controlled by the nutrient sensor adenosine monophosphate-activated protein kinase (AMPK), which drives the balance between oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we put forward a 51-node continuous mathematical model that describes the temporal evolution of the early events of activation, integrating a circuit of metabolic regulation into the main routes of signaling. The model simulates the induction of anergy due to defective co-stimulation, the CTLA-4 checkpoint blockade, and the differentiation to effector phenotypes induced by external cytokines. It also describes the adjustment of the OXPHOS-glycolysis equilibrium by the action of AMPK as the effector function of the T cell develops. The development of a transient phase of increased OXPHOS before induction of a sustained glycolytic phase during differentiation to the Th1, Th2 and Th17 phenotypes is shown. In contrast, during Treg differentiation, glycolysis is subsequently reduced as cell metabolism is predominantly polarized towards OXPHOS. These observations are in agreement with experimental data suggesting that OXPHOS produces an ATP reservoir before glycolysis boosts the production of metabolites needed for protein synthesis, cell function, and growth.
- Published
- 2021
24. Roles of Type VI Secretion System in Transport of Metal Ions
- Author
-
Xiaobing Yang, Hai Liu, Yanxiong Zhang, and Xihui Shen
- Subjects
Microbiology (medical) ,biology ,Metal ion transport ,Effector ,Chemistry ,Mini Review ,Metal ions in aqueous solution ,type VI secretion system ,metal ions ,regulation ,biology.organism_classification ,Microbiology ,QR1-502 ,Transmembrane protein ,transport ,Biophysics ,Extracellular ,Bacteria ,Function (biology) ,effectors ,Type VI secretion system - Abstract
The type VI secretion system (T6SS) is a transmembrane protein nanomachine employed by many gram-negative bacteria to directly translocate effectors into adjacent cells or the extracellular milieu, showing multiple functions in both interbacterial competition and bacteria-host interactions. Metal ion transport is a newly discovered T6SS function. This review summarizes the identified T6SS functions and highlights the features of metal ion transport mediated by T6SS and discusses its regulation.
- Published
- 2021
25. Screening Candidate Effectors of the Bean Bug Riptortus pedestris by Proteomic and Transcriptomic Analyses
- Author
-
Rui Ji, Yueying Wang, Hao Xu, Xiaoli Bing, Jinbu Li, Weichuan Fu, Cong Rao, and Xingzhou Liu
- Subjects
stink bug ,Genetics ,Saliva ,elicitor ,Ecology ,Evolution ,Effector ,legume ,Biology ,Transcriptome ,Open reading frame ,Proteome ,QH359-425 ,Plant defense against herbivory ,plant immunity ,ORFS ,Gene ,plant-insect interaction ,QH540-549.5 ,Ecology, Evolution, Behavior and Systematics - Abstract
The damage of Riptortus pedestris is exceptional by leading soybean plants to keep green in late autumn. Identification of the salivary proteins is essential to understand how the pest-plant interaction occurs. Here, we have tried to identify them by a combination of proteomic and transcriptomic analyses. The transcriptomes of salivary glands from R. pedestris males, females and nymphs showed about 28,000 unigenes, in which about 40% had open reading frames (ORFs). Therefore, the predicted proteins in the transcriptomes with secretion signals were obtained. Many of the top 1,000 expressed transcripts were involved in protein biosynthesis and transport, suggesting that the salivary glands produce a rich repertoire of proteins. In addition, saliva of R. pedestris males, females and nymphs was collected and proteins inside were identified. In total, 155, 20, and 11 proteins were, respectively, found in their saliva. We have tested the tissue-specific expression of 68 genes that are likely to be effectors, either because they are homologs of reported effectors of other sap-feeding arthropods, or because they are within the top 1,000 expressed genes or found in the salivary proteomes. Their potential functions in regulating plant defenses were discussed. The datasets reported here represent the first step in identifying effectors of R. pedestris.
- Published
- 2021
26. Unlocking the Role of Exercise on CD4+ T Cell Plasticity
- Author
-
David B Pyne, Thomasina Donovan, Nicole Vlahovich, and Chloé D Goldsmith
- Subjects
CD4-Positive T-Lymphocytes ,Immunosenescence ,T cell ,Cell Plasticity ,Immunology ,Mitochondrion ,Chromatin remodeling ,Epigenesis, Genetic ,chromatin remodeling ,medicine ,Animals ,Humans ,Immunology and Allergy ,histone modification ,Epigenetics ,Exercise ,Cellular Senescence ,DNA methylation ,epigenetics ,biology ,Effector ,RC581-607 ,Chromatin Assembly and Disassembly ,Mitochondria ,Phenotype ,Histone ,medicine.anatomical_structure ,Perspective ,biology.protein ,Immunologic diseases. Allergy ,immune ,Energy Metabolism ,metabolism ,Neuroscience ,Reprogramming - Abstract
A hallmark of T cell ageing is a loss of effector plasticity. Exercise delays T cell ageing, yet the mechanisms driving the effects of exercise on T cell biology are not well elucidated. T cell plasticity is closely linked with metabolism, and consequently sensitive to metabolic changes induced by exercise. Mitochondrial function is essential for providing the intermediate metabolites necessary to generate and modify epigenetic marks in the nucleus, thus metabolic activity and epigenetic mechanisms are intertwined. In this perspective we propose a role for exercise in CD4+ T cell plasticity, exploring links between exercise, metabolism and epigenetic reprogramming.
- Published
- 2021
- Full Text
- View/download PDF
27. Comprehensive Time-Series Analysis of the Gene Expression Profile in a Susceptible Cultivar of Tree Tomato (Solanum betaceum) During the Infection of Phytophthora betacei
- Author
-
Adriana Bernal, David Botero, Jorge Duitama, Daniel Bautista, Natalia Guayazan-Palacios, Martha Cárdenas, Silvia Restrepo, and Maria Camila Buitrago
- Subjects
Genetics ,biology ,Phytophthora betacei ,Host (biology) ,Effector ,plant–pathogen interaction ,food and beverages ,Plant culture ,Tree-tomato ,Plant Science ,biology.organism_classification ,food.food ,SB1-1110 ,Transcriptome ,food ,time series analysis ,Solanum betaceum ,Blight ,Phytophthora ,Solanum ,Pathogen ,plant response - Abstract
Solanum betaceum is a tree from the Andean region bearing edible fruits, considered an exotic export. Although there has been renewed interest in its commercialization, sustainability, and disease management have been limiting factors. Phytophthora betacei is a recently described species that causes late blight in S. betaceum. There is no general study of the response of S. betaceum, particularly, in the changes in expression of pathogenesis-related genes. In this manuscript we present a comprehensive RNA-seq time-series study of the plant response to the infection of P. betacei. Following six time points of infection, the differentially expressed genes (DEGs) involved in the defense by the plant were contextualized in a sequential manner. We documented 5,628 DEGs across all time-points. From 6 to 24 h post-inoculation, we highlighted DEGs involved in the recognition of the pathogen by the likely activation of pattern-triggered immunity (PTI) genes. We also describe the possible effect of the pathogen effectors in the host during the effector-triggered response. Finally, we reveal genes related to the susceptible outcome of the interaction caused by the onset of necrotrophy and the sharp transcriptional changes as a response to the pathogen. This is the first report of the transcriptome of the tree tomato in response to the newly described pathogen P. betacei.
- Published
- 2021
28. A Putative C2H2 Transcription Factor CgTF6, Controlled by CgTF1, Negatively Regulates Chaetoglobosin A Biosynthesis in Chaetomium globosum
- Author
-
Yu Yan, Biyun Xiang, Qiaohong Xie, Yamin Lin, Guangya Shen, Xiaoran Hao, and Xudong Zhu
- Subjects
Chaetomium globosum ,Effector ,secondary metabolites ,Mutant ,Regulator ,Plant culture ,chaetoglobosin A ,General Medicine ,Biology ,Cell biology ,SB1-1110 ,C2H2 ,Gene cluster ,Signal transduction ,Zn(II)2Cys6 ,Transcription factor ,Gene ,transcription factor - Abstract
Gα signaling pathway as well as the global regulator LaeA were demonstrated to positively regulate the biosynthesis of chaetoglobosin A (ChA), a promising biotic pesticide produced by Chaetomium globosum. Recently, the regulatory function of Zn2Cys6 binuclear finger transcription factor CgcheR that lies within the ChA biosynthesis gene cluster has been confirmed. However, CgcheR was not merely a pathway specific regulator. In this study, we showed that the homologs gene of CgcheR (designated as Cgtf1) regulate ChA biosynthesis and sporulation in C. globosum NK102. More importantly, RNA-seq profiling demonstrated that 1,388 genes were significant differentially expressed as Cgtf1 deleted. Among them, a putative C2H2 transcription factor, named Cgtf6, showed the highest gene expression variation in zinc-binding proteins encoding genes as Cgtf1 deleted. qRT-PCR analysis confirmed that expression of Cgtf6 was significantly reduced in CgTF1 null mutants. Whereas, deletion of Cgtf6 resulted in the transcriptional activation and consequent increase in the expression of ChA biosynthesis gene cluster and ChA production in C. globosum. These data suggested that CgTF6 probably acted as an end product feedback effector, and interacted with CgTF1 to maintain a tolerable concentration of ChA for cell survival.
- Published
- 2021
- Full Text
- View/download PDF
29. A Valsa mali Effector Protein 1 Targets Apple (Malus domestica) Pathogenesis-Related 10 Protein to Promote Virulence
- Author
-
Weidong Wang, Jiajun Nie, Luqiong Lv, Wan Gong, Shuaile Wang, Mingming Yang, Liangsheng Xu, Mingjun Li, Hongxia Du, and Lili Huang
- Subjects
Malus ,callose deposition ,biology ,Effector ,fungi ,Plant culture ,Virulence ,Plant Science ,defense response ,biology.organism_classification ,Virulence factor ,SB1-1110 ,Microbiology ,Bimolecular fluorescence complementation ,Immune system ,parasitic diseases ,Valsa mali ,Secretion ,plant immunity ,PR10 ,Valsa - Abstract
To successfully colonize the plants, the pathogenic microbes secrete a mass of effector proteins which manipulate host immunity. Apple valsa canker is a destructive disease caused by the weakly parasitic fungus Valsa mali. A previous study indicated that the V. mali effector protein 1 (VmEP1) is an essential virulence factor. However, the pathogenic mechanism of VmEP1 in V. mali remains poorly understood. In this study, we found that the apple (Malus domestica) pathogenesis-related 10 proteins (MdPR10) are the virulence target of VmEP1 using a yeast two-hybrid screening. By bimolecular fluorescence (BiFC) and coimmunoprecipitation (Co-IP), we confirmed that the VmEP1 interacts with MdPR10 in vivo. Silencing of MdPR10 notably enhanced the V. mali infection, and overexpression of MdPR10 markedly reduced its infection, which corroborates its positive role in plant immunity against V. mali. Furthermore, we showed that the co-expression of VmEP1 with MdPR10 compromised the MdPR10-mediated resistance to V. mali. Taken together, our results revealed a mechanism by which a V. mali effector protein suppresses the host immune responses by interfering with the MdPR10-mediated resistance to V. mali during the infection.
- Published
- 2021
- Full Text
- View/download PDF
30. Interaction of Phytophthora sojae Effector Avr1b With E3 Ubiquitin Ligase GmPUB1 Is Required for Recognition by Soybeans Carrying Phytophthora Resistance Rps1-b and Rps1-k Genes
- Author
-
Hargeet K. Brar, Regina Hanlon, Hongyu Gao, Hua Wise, Madan K. Bhattacharyya, Chunyu Liao, Eli Perez, Lecong Zhou, Brett M. Tyler, Shan Li, and Narinder Pal
- Subjects
RXLR effector ,biology ,Effector ,Plant culture ,Plant Science ,biology.organism_classification ,E3 ubiquitin-ligase ,SB1-1110 ,Ubiquitin ligase ,Cell biology ,Bimolecular fluorescence complementation ,Phytophthora sojae ,Ubiquitin ,oomycete ,biology.protein ,Gene silencing ,Phytophthora ,soybean U-box protein ,plant immunity ,Gene - Abstract
Phytophthora sojae is an oomycete that causes stem and root rot disease in soybean. P. sojae delivers many RxLR effector proteins, including Avr1b, into host cells to promote infection. We show here that Avr1b interacts with the soybean U-box protein, GmPUB1-1, in yeast two-hybrid, pull down, and bimolecular fluorescence complementation (BIFC) assays. GmPUB1-1, and a homeologous copy GmPUB1-2, are induced by infection and encode 403 amino acid proteins with U-Box domains at their N-termini. Non-synonymous mutations in the Avr1b C-terminus that abolish suppression of cell death also abolished the interaction of Avr1b with GmPUB1-1, while deletion of the GmPUB1-1 C-terminus, but not the U box, abolished the interaction. BIFC experiments suggested that the GmPUB1-1-Avr1b complex is targeted to the nucleus. In vitro ubiquitination assays demonstrated that GmPUB1-1 possesses E3 ligase activity. Silencing of the GmPUB1 genes in soybean cotyledons resulted in loss of recognition of Avr1b by gene products encoded by Rps1-b and Rps1-k. The recognition of Avr1k (which did not interact with GmPUB1-1) by Rps1-k plants was not, however, affected following GmPUB1-1 silencing. Furthermore, over-expression of GmPUB1-1 in particle bombardment experiments triggered cell death suggesting that GmPUB1 may be a positive regulator of effector-triggered immunity. In a yeast two-hybrid system, GmPUB1-1 also interacted with a number of other RxLR effectors including Avr1d, while Avr1b and Avr1d interacted with a number of other infection-induced GmPUB proteins, suggesting that the pathogen uses a multiplex of interactions of RxLR effectors with GmPUB proteins to modulate host immunity.
- Published
- 2021
- Full Text
- View/download PDF
31. Integration of Transcriptomics and Proteomics Improves the Characterization of the Role of Mussel Gills in a Bacterial Waterborne Infection
- Author
-
Amaro Saco, Antonella Panebianco, Sofía Blanco, Beatriz Novoa, Angel P. Diz, Antonio Figueras, and European Commission
- Subjects
Science ,mussel ,Quantitative proteomics ,Ocean Engineering ,QH1-199.5 ,Biology ,Aquatic Science ,Proteomics ,Tandem mass tag ,Oceanography ,Transcriptome ,03 medical and health sciences ,mollusc ,Immune system ,14. Life underwater ,proteomic ,030304 developmental biology ,Water Science and Technology ,0303 health sciences ,Global and Planetary Change ,Innate immune system ,Effector ,030302 biochemistry & molecular biology ,bacterial infection ,General. Including nature conservation, geographical distribution ,transcriptomic ,biology.organism_classification ,Mytilus ,Cell biology ,immune - Abstract
17 pages, 6 figures, 2 tables.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), In recent years, the immune response of mussels (Mytilus galloprovincialis) has been studied at the transcriptomic level against several bacterial infections. As a result, different immune mechanisms have been revealed, including both conserved essential innate pathways and particularities of the mussel immune response according to its nature and environment. However, there is often a lack of functional verification because mussels are a non-model species and because transcriptomic and proteomic information is not always well correlated. In the current study, a high-throughput quantitative proteomics study coupled to LC-MS/MS analysis using isobaric tandem mass tags (TMTs) for protein labeling was employed to study the mussel gill immune response to a Vibrio splendidus bath (waterborne) infection at a functional protein level. A total of 4,242 proteins were identified and quantified, of which 226 were differentially expressed (DEPs) after infection, giving to the study a depth that was lacking in previous proteomic studies of the bivalve immune response. Modulated proteins evidenced an important cytoskeletal disruption caused by bacterial infection. A conserved network of associated proteins was modulated, regulating oxidative stress and NF-kB inflammatory responses and leading to innate immunity effectors. Proteomic results were submitted to an integrated analysis with those obtained in a previous transcriptomic approach with the same infection. Half of all the quantified proteins had a concordant transcriptomic expression trend, but this concordance increased when focusing on the DEPs. The correlation was higher within the immune-related DEPs, and the activation of the conserved NF-kB pro-inflammatory pathway was the main response in both approaches. The results of both techniques could be integrated to obtain a more complete vision of the response, This research was funded by the Spanish AEI/EU-FEDER (RTI2018-095997-B-I00); the European Regional Development Fund (ERDF) Interreg V Spain—Portugal (0474_BLUEBIOLAB); the Consellería de Economía, Emprego e Industria—GAIN, Xunta de Galicia, project IN607B 2019/01 and EU H2020; project VIVALDI (678589); Xunta de Galicia (ED431C 2020/05) and FONDOS FEDER. AS was supported by a Spanish AEI/EU-FSE predoctoral contract PRE2019-090760
- Published
- 2021
- Full Text
- View/download PDF
32. Regulatory T Cells: Regulation of Identity and Function
- Author
-
Mark I. Greene, Payal Grover, and Peeyush N. Goel
- Subjects
FOXP3 ,antitumor immunity ,Immunology ,chemical and pharmacologic phenomena ,Review ,T-effector cells ,T-Lymphocytes, Regulatory ,Immune system ,Antigen ,Animals ,Humans ,Immunology and Allergy ,Secretion ,biology ,Effector ,Peripheral tolerance ,Forkhead Transcription Factors ,autoimmune ,immunosuppression mechanisms ,RC581-607 ,Treg-regulatory T cells ,Cell biology ,Tip60 ,Perforin ,Granzyme ,biology.protein ,Immunologic diseases. Allergy - Abstract
T regulatory cells suppress a variety of immune responses to self-antigens and play a role in peripheral tolerance maintenance by limiting autoimmune disorders, and other pathological immune responses such as limiting immune reactivity to oncoprotein encoded antigens. Forkhead box P3 (FOXP3) expression is required for Treg stability and affects functional activity. Mutations in the master regulator FOXP3 and related components have been linked to autoimmune diseases in humans, such as IPEX, and a scurfy-like phenotype in mice. Several lines of evidence indicate that Treg use a variety of immunosuppressive mechanisms to limit an immune response by targeting effector cells, including secretion of immunoregulatory cytokines, granzyme/perforin-mediated cell cytolysis, metabolic perturbation, directing the maturation and function of antigen-presenting cells (APC) and secretion of extracellular vesicles for the development of immunological tolerance. In this review, several regulatory mechanisms have been highlighted and discussed.
- Published
- 2021
33. Macrophages Control the Bioavailability of Vitamin D and Vitamin D-Regulated T Cell Responses
- Author
-
Daniel Villalba Lopez, Martin Kongsbak-Wismann, Anders Woetmann, Charlotte M. Bonefeld, Niels Ødum, Carsten Geisler, and Fatima A H Al-Jaberi
- Subjects
Vitamin ,Vitamin D-binding protein ,T cell ,Immunology ,T cells ,Biological Availability ,Inflammation ,T-Lymphocytes, Regulatory ,DBP ,chemistry.chemical_compound ,medicine ,Vitamin D and neurology ,Humans ,Immunology and Allergy ,Vitamin D ,Original Research ,25-Hydroxyvitamin D3 1-alpha-Hydroxylase ,Chemistry ,Effector ,Vitamin D-Binding Protein ,RC581-607 ,Molecular biology ,cytokines ,macrophages ,Bioavailability ,medicine.anatomical_structure ,Immunologic diseases. Allergy ,medicine.symptom ,Function (biology) - Abstract
The active form of vitamin D3 (1,25(OH)2D3) has a great impact on T cell effector function. Thus, 1,25(OH)2D3 promotes T helper 2 (Th2) and regulatory T (Treg) cell function and concomitantly inhibits Th1 and Th17 cell function. Thus, it is believed that vitamin D exerts anti-inflammatory effects. However, vitamin D binding protein (DBP) strongly binds both 1,25(OH)2D3 and the precursor 25(OH)D3, leaving only a minor fraction of vitamin D in the free, bioavailable form. Accordingly, DBP in physiological concentrations would be expected to block the effect of vitamin D on T cells and dendritic cells. In the present study, we show that pro-inflammatory, monocyte-derived M1 macrophages express very high levels of the 25(OH)D-1α-hydroxylase CYP27B1 that enables them to convert 25(OH)D3 into 1,25(OH)2D3 even in the presence of physiological concentrations of DBP. Co-cultivation of M1 macrophages with T cells allows them to overcome the sequestering of 25(OH)D3 by DBP and to produce sufficient levels of 1,25(OH)2D3 to affect T cell effector function. This study suggests that in highly inflammatory conditions, M1 macrophages can produce sufficient levels of 1,25(OH)2D3 to modify T cell responses and thereby reduce T cell-mediated inflammation via a vitamin D-mediated negative feed-back loop.
- Published
- 2021
34. Quantitative Analyses Reveal How Hypoxia Reconfigures the Proteome of Primary Cytotoxic T Lymphocytes
- Author
-
Sarah H. Ross, Christina M. Rollings, and Doreen A. Cantrell
- Subjects
quantitative proteomics ,Proteome ,medicine.medical_treatment ,Immunology ,oxygen sensing ,Mice, Transgenic ,CD8 T cells ,Mass Spectrometry ,CTLs ,Mice ,cytotoxic lymphocytes ,Immune system ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Receptor ,Transcription factor ,Cells, Cultured ,Original Research ,hypoxia ,Effector ,Chemistry ,Membrane Proteins ,Molecular Sequence Annotation ,Cell Cycle Checkpoints ,RC581-607 ,Cell Hypoxia ,Cell biology ,Gene Ontology ,Cytokine ,Gene Expression Regulation ,Protein Biosynthesis ,Lactates ,Interleukin-2 ,Female ,Immunologic diseases. Allergy ,Genes, T-Cell Receptor alpha ,CD8 ,Chromatography, Liquid ,T-Lymphocytes, Cytotoxic - Abstract
Metabolic and nutrient-sensing pathways play an important role in controlling the efficacy of effector T cells. Oxygen is a critical regulator of cellular metabolism. However, during immune responses T cells must function in oxygen-deficient, or hypoxic, environments. Here, we used high resolution mass spectrometry to investigate how the proteome of primary murine CD8+ cytotoxic T lymphocytes (CTLs) is reconfigured in response to hypoxia in vitro. We identified and quantified over 7,600 proteins and discovered that hypoxia increased the abundance of a selected number of proteins in CTLs. This included glucose transporters, metabolic enzymes, transcription factors, cytolytic effector molecules, checkpoint receptors and adhesion molecules. While some of these proteins may augment the effector functions of CTLs, others may limit their cytotoxicity. Moreover, we determined that hypoxia could inhibit IL-2-induced proliferation cues and antigen-induced pro-inflammatory cytokine production in CTLs. These data provide a comprehensive resource for understanding the magnitude of the CTL response to hypoxia and emphasise the importance of oxygen-sensing pathways for controlling CD8+ T cells. Additionally, this study provides new understanding about how hypoxia may promote the effector function of CTLs, while contributing to their dysfunction in some contexts.
- Published
- 2021
35. Pulmonary-Resident Memory Lymphocytes: Pivotal Orchestrators of Local Immunity Against Respiratory Infections
- Author
-
Vincent Pavot, Kevin Dhaliwal, Duncan Humphries, Richard A. O’Connor, Daniel Larocque, and Martine Chabaud-Riou
- Subjects
Immunology ,Context (language use) ,Review ,Biology ,EVLP ,lung ,resident memory T cells ,Memory T Cells ,Memory B Cells ,Antigen ,Immunity ,resident memory B cells ,medicine ,Animals ,Humans ,Immunology and Allergy ,Respiratory Tract Infections ,in situ optical imaging ,Lung ,Effector ,Respiratory infection ,Viral Vaccines ,Bacterial Infections ,RC581-607 ,vaccination ,infection ,Vaccination ,Phenotype ,medicine.anatomical_structure ,Immunization ,Virus Diseases ,Bacterial Vaccines ,Host-Pathogen Interactions ,Immunologic diseases. Allergy ,Immunologic Memory - Abstract
There is increasing evidence that lung-resident memory T and B cells play a critical role in protecting against respiratory reinfection. With a unique transcriptional and phenotypic profile, resident memory lymphocytes are maintained in a quiescent state, constantly surveying the lung for microbial intruders. Upon reactivation with cognate antigen, these cells provide rapid effector function to enhance immunity and prevent infection. Immunization strategies designed to induce their formation, alongside novel techniques enabling their detection, have the potential to accelerate and transform vaccine development. Despite most data originating from murine studies, this review will discuss recent insights into the generation, maintenance and characterisation of pulmonary resident memory lymphocytes in the context of respiratory infection and vaccination using recent findings from human and non-human primate studies.
- Published
- 2021
36. Contribution to HIV Prevention and Treatment by Antibody-Mediated Effector Function and Advances in Broadly Neutralizing Antibody Delivery by Vectored Immunoprophylaxis
- Author
-
Meredith Phelps and Alejandro B. Balazs
- Subjects
Genetic Vectors ,Immunology ,Fc receptor ,HIV Infections ,Review ,Virus ,Epitope ,broadly neutralizing antibody ,Phagocytosis ,Viral envelope ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Complement Activation ,innate immunity ,Antibody-dependent cell-mediated cytotoxicity ,biology ,Effector ,business.industry ,Antibody-Dependent Cell Cytotoxicity ,Immunization, Passive ,HIV ,AAV ,Genetic Therapy ,Dependovirus ,RC581-607 ,Virology ,vectored immunoprophylaxis ,Treatment Outcome ,humanized mice ,VRC07 ,Host-Pathogen Interactions ,biology.protein ,Immunologic diseases. Allergy ,Antibody ,business ,Viral load ,Broadly Neutralizing Antibodies - Abstract
HIV-1 broadly neutralizing antibodies (bNAbs) targeting the viral envelope have shown significant promise in both HIV prevention and viral clearance, including pivotal results against sensitive strains in the recent Antibody Mediated Prevention (AMP) trial. Studies of bNAb passive transfer in infected patients have demonstrated transient reduction of viral load at high concentrations that rebounds as bNAb is cleared from circulation. While neutralization is a crucial component of therapeutic efficacy, numerous studies have demonstrated that bNAbs can also mediate effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). These functions have been shown to contribute towards protection in several models of HIV acquisition and in viral clearance during chronic infection, however the role of target epitope in facilitating these functions, as well as the contribution of individual innate functions in protection and viral clearance remain areas of active investigation. Despite their potential, the transient nature of antibody passive transfer limits the widespread use of bNAbs. To overcome this, we and others have demonstrated vectored antibody delivery capable of yielding long-lasting expression of bNAbs in vivo. Two clinical trials have shown that adeno-associated virus (AAV) delivery of bNAbs is safe and capable of sustained bNAb expression for over 18 months following a single intramuscular administration. Here, we review key concepts of effector functions mediated by bNAbs against HIV infection and the potential for vectored immunoprophylaxis as a means of producing bNAbs in patients.
- Published
- 2021
37. A Novel, Small Cysteine-Rich Effector, RsSCR10 in Rhizoctonia solani Is Sufficient to Trigger Plant Cell Death
- Author
-
Xianyu Niu, Guijing Yang, Hui Lin, Yao Liu, Ping Li, and Aiping Zheng
- Subjects
Signal peptide ,chemistry.chemical_classification ,Microbiology (medical) ,Agroinfiltration ,Programmed cell death ,biology ,Effector ,N. benthamiana ,SCR secreted protein ,food and beverages ,Nicotiana benthamiana ,biology.organism_classification ,Microbiology ,immune response ,QR1-502 ,Elicitor ,Amino acid ,Rhizoctonia solani ,cell death ,chemistry ,R. solani AG1IA ,protein interaction - Abstract
The necrotrophic phytopathogen Rhizoctonia solani (R. solani) is a fungus that causes disease in a wide range of plant species. Fungal genomes encode abundant, small cysteine-rich (SCR) secreted proteins, and the probable importance of these to pathogenesis has been highlighted in various pathogens. However, there are currently no reports of an R. solani SCR-secreted protein with evidential elicitor activity. In this study, the molecular function of 10 SCR-secreted protein genes from R. solani was explored by agroinfiltration into Nicotiana benthamiana (N. benthamiana) leaves, and a novel SCR protein RsSCR10 was identified that triggered cell death and oxidative burst in tobacco. RsSCR10 comprises 84 amino acids, including a signal peptide (SP) of 19 amino acids that is necessary for RsSCR10 to induce tobacco cell death. Elicitation of cell death by RsSCR10 was dependent on Hsp90 but not on RAR1, proving its effector activity. Two cysteine residues have important effects on the function of RsSCR10 in inducing cell death. Furthermore, RsSCR10 showed cross-interaction with five rice molecules, and the inferred functions of these rice proteins suggest they are instrumental in how the host copes with adversity. Overall, this study demonstrates that RsSCR10 is a potential effector that has a critical role in R. solani AG1 IA-host interactions.
- Published
- 2021
- Full Text
- View/download PDF
38. Emerging Complexity in CD4+T Lineage Programming and Its Implications in Colorectal Cancer
- Author
-
Daniel DiToro and Rajatava Basu
- Subjects
CD4-Positive T-Lymphocytes ,Transcription, Genetic ,Colorectal cancer ,T cell ,Cell Plasticity ,Immunology ,Inflammation ,Context (language use) ,Review ,Biology ,Lymphocytes, Tumor-Infiltrating ,Immune system ,colorectal carcinoma ,effector T cell ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cell Lineage ,CD4+T cell ,Mechanism (biology) ,Effector ,regulatory T cell (Treg) ,lineage programming, plasticity ,Cell Differentiation ,T helper cell ,RC581-607 ,Prognosis ,medicine.disease ,T follicular regulatory cell (Tfr) ,Gene Expression Regulation, Neoplastic ,Phenotype ,medicine.anatomical_structure ,Cancer research ,Immunologic diseases. Allergy ,T follicular helper cell (Tfh) ,medicine.symptom ,Colorectal Neoplasms - Abstract
The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.
- Published
- 2021
39. Novel Effector RHIFs Identified From Acidovorax avenae Strains N1141 and K1 Play Different Roles in Host and Non-host Plants
- Author
-
Minami Nakamura, Machiko Kondo, Aika Suzuki, Hiroyuki Hirai, and Fang-Sik Che
- Subjects
hypersensitive response cell death ,Infectivity ,Hypersensitive response ,Programmed cell death ,symptom formation ,biology ,Acidovorax ,Effector ,rice ,Mutant ,Plant culture ,food and beverages ,p-loop NTPase ,Plant Science ,biology.organism_classification ,pathogen effector ,SB1-1110 ,Microbiology ,effector-triggered immunity ,Secretion ,Effector-triggered immunity - Abstract
Plant pathogenic bacteria inject effectors into plant cells using type III secretion systems (T3SS) to evade plant immune systems and facilitate infection. In contrast, plants have evolved defense systems called effector-triggered immunity (ETI) that can detect such effectors during co-evolution with pathogens. The rice-avirulent strain N1141 of the bacterial pathogen Acidovorax avenae causes rice ETI, including hypersensitive response (HR) cell death in a T3SS-dependent manner, suggesting that strain N1141 expresses an ETI-inducing effector. By screening 6,200 transposon-tagged N1141 mutants based on their ability to induce HR cell death, we identified 17 mutants lacking this ability. Sequence analysis and T3SS-mediated intracellular transport showed that a protein called rice HR cell death inducing factor (RHIF) is a candidate effector protein that causes HR cell death in rice. RHIF-disrupted N1141 lacks the ability to induce HR cell death, whereas RHIF expression in this mutant complemented this ability. In contrast, RHIF from rice-virulent strain K1 functions as an ETI inducer in the non-host plant finger millet. Furthermore, inoculation of rice and finger millet with either RHIF-deficient N1141 or K1 strains showed that a deficiency of RHIF genes in both strains results in decreased infectivity toward each the host plants. Collectively, novel effector RHIFs identified from A. avenae strains N1141 and K1 function in establishing infection in host plants and in ETI induction in non-host plants.
- Published
- 2021
40. ‘Candidatus Liberibacter asiaticus’ Multimeric LotP Mediates Citrus sinensis Defense Response Activation
- Author
-
Claudio F. Gonzalez, Kaylie A. Padgett-Pagliai, María Rosa Marano, Graciela L. Lorca, Lucila Garcia, Alexandra E. Cuaycal, and Marcelo L. Merli
- Subjects
0106 biological sciences ,0301 basic medicine ,Microbiology (medical) ,Proteases ,medicine.medical_treatment ,Biology ,01 natural sciences ,Microbiology ,Interactome ,03 medical and health sciences ,proteomics ,Huanglongbing (HLB) ,citrus greening disease ,Plant defense against herbivory ,medicine ,effector protein ,Protease ,Effector ,food and beverages ,GroEL ,QR1-502 ,Cell biology ,030104 developmental biology ,Proteostasis ,Citrus greening disease ,pathogen ,010606 plant biology & botany - Abstract
‘Candidatus Liberibacter asiaticus’ is known as the most pathogenic organism associated with citrus greening disease. Since its publicized emergence in Florida in 2005, ‘Ca. L. asiaticus’ remains unculturable. Currently, a limited number of potential disease effectors have been identified through in silico analysis. Therefore, these potential effectors remain poorly characterized and do not fully explain the complexity of symptoms observed in citrus trees infected with ‘Ca. L. asiaticus.’ LotP has been identified as a potential effector and have been partially characterized. This protein retains structural homology to the substrate binding domain of the Lon protease. LotP interacts with chaperones like GroEL, Hsp40, DnaJ, and ClpX and may exercise its biological role through interactions with different proteins involved in proteostasis networks. Here, we evaluate the interactome of LotP—revealing a new protein–protein interaction target (Lon-serine protease) and its effect on citrus plant tissue integrity. We found that via protein–protein interactions, LotP can enhance Lon protease activity, increasing the degradation rate of its specific targets. Infiltration of purified LotP strained citrus plant tissue causing photoinhibition and chlorosis after several days. Proteomics analysis of LotP tissues recovering after the infiltration revealed a large abundance of plant proteins associated with the stabilization and processing of mRNA transcripts, a subset of important transcription factors; and pathways associated with innate plant defense were highly expressed. Furthermore, interactions and substrate binding module of LotP suggest potential interactions with plant proteins, most likely proteases.
- Published
- 2021
41. Immune Equilibrium Depends on the Interaction Between Recognition and Presentation Landscapes
- Author
-
Vladimir A. Kozlov, Valeriy Tereshchenko, and Daniil Shevyrev
- Subjects
T-cell receptor repertoire ,0301 basic medicine ,antigen presentation/recognition ,immunopeptidome ,a rank-size frequency distribution of T- and B-cell receptors ,T-Lymphocytes ,Immunology ,Review ,Computational biology ,Biology ,Major histocompatibility complex ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Immunity ,medicine ,Animals ,Humans ,Immunology and Allergy ,homeostatic proliferation ,B cell ,Antigen Presentation ,B-Lymphocytes ,Effector ,T-cell receptor ,immune equilibrium ,B-cell receptor repertoire ,adaptive immunity ,RC581-607 ,Acquired immune system ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Immunologic diseases. Allergy ,030215 immunology - Abstract
In this review, we described the structure and organization of antigen-recognizing repertoires of B and T cells from the standpoint of modern immunology. We summarized the latest advances in bioinformatics analysis of sequencing data from T and B cell repertoires and also presented contemporary ideas about the mechanisms of clonal diversity formation at different stages of organism development. At the same time, we focused on the importance of the allelic variants of the HLA genes and spectra of presented antigens for the formation of T-cell receptors (TCR) landscapes. The main idea of this review is that immune equilibrium and proper functioning of immunity are highly dependent on the interaction between the recognition and the presentation landscapes of antigens. Certain changes in these landscapes can occur during life, which can affect the protective function of adaptive immunity. We described some mechanisms associated with these changes, for example, the conversion of effector cells into regulatory cells and vice versa due to the trans-differentiation or bystander effect, changes in the clonal organization of the general TCR repertoire due to homeostatic proliferation or aging, and the background for the altered presentation of some antigens due to SNP mutations of MHC, or the alteration of the presenting antigens due to post-translational modifications. The authors suggest that such alterations can lead to an increase in the risk of the development of oncological and autoimmune diseases and influence the sensitivity of the organism to different infectious agents.
- Published
- 2021
42. CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection
- Author
-
Rebecca T. Veenhuis, Caroline C. Garliss, Justin R. Bailey, and Joel N. Blankson
- Subjects
0301 basic medicine ,Immunology ,synergy ,HIV Infections ,Viremia ,CD8-Positive T-Lymphocytes ,HIV Antibodies ,Biology ,Virus Replication ,elite controllers ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Cells, Cultured ,Original Research ,Effector ,HIV ,elite suppressors ,RC581-607 ,broadly neutralising antibodies ,medicine.disease ,Virology ,CD8 lymphocytes + ,In vitro ,030104 developmental biology ,Viral replication ,030220 oncology & carcinogenesis ,biology.protein ,Immunologic diseases. Allergy ,Antibody ,Broadly Neutralizing Antibodies ,CD8 ,Function (biology) - Abstract
HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long term control of viral replication. In this study we demonstrate a synergistic interaction between CD8 T cells and bNAbs using an in vitro model. Our data suggest that this combinatorial approach is very effective at suppressing viral replication in vitro and should be considered in future therapeutic studies.
- Published
- 2021
43. Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren’s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule
- Author
-
Anneline C. Hinrichs, Sofie L. M. Blokland, Ana P. Lopes, Catharina G. K. Wichers, Aike A. Kruize, Aridaman Pandit, Timothy R. D. J. Radstake, and Joel A. G. van Roon
- Subjects
Adult ,Male ,0301 basic medicine ,Chemokine ,medicine.medical_treatment ,T cell ,Immunology ,Primary Sjögren’s syndrome ,CCL5 ,CXCR5 ,Transcriptome ,transcriptomics ,Receptors, CCR ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Antigen ,T-Lymphocyte Subsets ,medicine ,Humans ,Immunology and Allergy ,Chemokine CCL5 ,Original Research ,Aged ,030203 arthritis & rheumatology ,biology ,Effector ,Gene Expression Profiling ,autoimmunity ,T-Lymphocytes, Helper-Inducer ,RC581-607 ,Middle Aged ,CCR9+ Th cells ,Molecular biology ,stomatognathic diseases ,Sjogren's Syndrome ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,biology.protein ,Female ,Immunologic diseases. Allergy - Abstract
IntroductionCCR9+ Tfh-like pathogenic T helper (Th) cells are elevated in patients with primary Sjögren’s syndrome (pSS) and indicated to play a role in pSS immunopathology. Here we delineate the CCR9+ Th cell-specific transcriptome to study the molecular dysregulation of these cells in pSS patients.MethodsCCR9+, CXCR5+ and CCR9-CXCR5- Th cells from blood of 7 healthy controls (HC) and 7 pSS patients were FACS sorted and RNA sequencing was performed. Computational analysis was used to identify differentially expressed genes (DEGs), coherent gene expression networks and differentially regulated pathways. Target genes were replicated in additional cohorts.Results5131 genes were differentially expressed between CCR9+ and CXCR5+ Th cells; 6493 and 4783 between CCR9+ and CCR9-CXCR5- and between CXCR5+ and CCR9-CXCR5-, respectively. In the CCR9+ Th cell subset 2777 DEGs were identified between HC and pSS patients, 1416 and 1077 in the CXCR5+ and CCR9-CXCR5- subsets, respectively. One gene network was selected based on eigengene expression differences between the Th cell subsets and pathways enriched for genes involved in migration and adhesion, cytokine and chemokine production. Selected DEGs of interest (HOPX, SOX4, ITGAE, ITGA1, NCR3, ABCB1, C3AR1, NT5E, CCR5 and CCL5) from this module were validated and found upregulated in blood CCR9+ Th cells, but were similarly expressed in HC and pSS patients. Increased frequencies of CCR9+ Th cells were shown to express higher levels of CCL5 than CXCR5+ and CCR9-CXCR5- Th cells, with the highest expression confined to effector CCR9+ Th cells. Antigenic triggering and stimulation with IL-7 of the Th cell subsets co-cultured with monocytes strongly induced CCL5 secretion in CCR9+ Th cell cocultures. Additionally, effector CCR9+ Th cells rapidly released CCL5 and secreted the highest CCL5 levels upon stimulation.ConclusionTranscriptomic analysis of circulating CCR9+ Th cells reveals CCR9-specific pathways involved in effector T cell function equally expressed in pSS patients and HC. Given the increased numbers of CCR9+ Th cells in the blood and inflamed glands of pSS patients and presence of inflammatory stimuli to activate these cells this suggests that CCR9-specific functions, such as cell recruitment upon CCL5 secretion, could significantly contribute to immunopathology in pSS.
- Published
- 2021
44. Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks
- Author
-
Stephan Menne, Severin O. Gudima, Manasa Suresh, Marta G. Murreddu, and Bin Li
- Subjects
0301 basic medicine ,Inflammasomes ,viruses ,Receptor expression ,Immunology ,Gene Expression ,medicine.disease_cause ,03 medical and health sciences ,Hepatitis B, Chronic ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Hepatitis B Virus, Woodchuck ,Immunology and Allergy ,chronic hepatitis B ,Receptors, Immunologic ,Receptor ,Original Research ,Hepatitis B virus ,acute hepatitis B ,Innate immune system ,woodchuck ,biology ,Effector ,Woodchuck hepatitis virus ,pattern recognition receptors ,Pattern recognition receptor ,virus diseases ,RC581-607 ,Viral Load ,biochemical phenomena, metabolism, and nutrition ,Hepatitis B ,biology.organism_classification ,Immunity, Innate ,030104 developmental biology ,Liver ,Marmota ,innate immune response ,Disease Progression ,030211 gastroenterology & hepatology ,Immunologic diseases. Allergy ,hepatitis B virus ,Biomarkers ,Transcription Factors - Abstract
The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3–4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.
- Published
- 2021
45. Monocytes and Macrophages in COVID-19
- Author
-
Rainer Knoll, Joachim L. Schultze, and Jonas Schulte-Schrepping
- Subjects
0301 basic medicine ,medicine.medical_treatment ,immunology [HLA-DR Antigens] ,Review ,Disease ,Severity of Illness Index ,pathology [COVID-19] ,immunology [Inflammation] ,0302 clinical medicine ,immunology [SARS-CoV-2] ,Immunology and Allergy ,Macrophage ,immunology [COVID-19] ,Effector ,hyperinflammation ,immunology [Macrophages] ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,Viral disease ,medicine.symptom ,monocytes ,Immunology ,Inflammation ,macrophage ,immunology [Monocytes] ,03 medical and health sciences ,scRNA-seq ,medicine ,Humans ,ddc:610 ,pathology [Inflammation] ,pathology [Monocytes] ,SARS-CoV-2 ,business.industry ,Macrophages ,Monocyte ,COVID-19 ,HLA-DR Antigens ,RC581-607 ,030104 developmental biology ,Alveolar macrophage ,viral infection ,alveolar macrophage ,Immunologic diseases. Allergy ,business ,pathology [Macrophages] - Abstract
COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease’s pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.
- Published
- 2021
46. Genome Editing Technologies as Cellular Defense Against Viral Pathogens
- Author
-
Yingzi Zhang and Mo Li
- Subjects
0301 basic medicine ,QH301-705.5 ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Review ,Biology ,medicine.disease_cause ,Dengue fever ,Cell and Developmental Biology ,03 medical and health sciences ,CRISPR/Cas ,0302 clinical medicine ,Genome editing ,medicine ,genome editing ,CRISPR ,emerging pathogen ,Biology (General) ,Hepatitis B virus ,Transcription activator-like effector nuclease ,SARS-CoV-2 ,Effector ,HIV ,Cell Biology ,Hepatitis B ,medicine.disease ,Virology ,030104 developmental biology ,hepatitis B ,viral infectious disease ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Viral infectious diseases are significant threats to the welfare of world populations. Besides the widespread acute viral infections (e.g., dengue fever) and chronic infections [e.g., those by the human immunodeficiency virus (HIV) and hepatitis B virus (HBV)], emerging viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose great challenges to the world. Genome editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) proteins, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), have played essential roles in the study of new treatment for viral infectious diseases in cell lines, animal models, and clinical trials. Genome editing tools have been used to eliminate latent infections and provide resistance to new infections. Increasing evidence has shown that genome editing-based antiviral strategy is simple to design and can be quickly adapted to combat infections by a wide spectrum of viral pathogens, including the emerging coronaviruses. Here we review the development and applications of genome editing technologies for preventing or eliminating infections caused by HIV, HBV, HPV, HSV, and SARS-CoV-2, and discuss how the latest advances could enlighten further development of genome editing into a novel therapy for viral infectious diseases.
- Published
- 2021
47. Editorial: Immunity to Fungal Infections: Insights From the Innate Immune Recognition and Antifungal Effector Mechanisms
- Author
-
David L. Moyes, Allan J. Guimarães, and Rodrigo T. Figueiredo
- Subjects
lymphocytes ,Microbiology (medical) ,Antifungal ,Innate immune system ,leukocytes ,Effector ,medicine.drug_class ,Biology ,Microbiology ,cytokines ,QR1-502 ,Editorial ,Immunity ,Immunology ,medicine ,mycoses ,innate immunity - Published
- 2021
48. PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection
- Author
-
Roberto Tinoco, Emily N. Neubert, Linda M. Bradley, Monique L. Henriquez, and Christopher J. Stairiker
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Adoptive cell transfer ,T cell ,Immunology ,CD8-Positive T-Lymphocytes ,Lymphocytic Choriomeningitis ,Biology ,Lymphocyte Activation ,effector T cells ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,memory T cells ,Precursor cell ,virus infection ,medicine ,Animals ,Lymphocytic choriomeningitis virus ,Immunology and Allergy ,PSGL-1 ,LCMV ,Original Research ,Mice, Knockout ,Membrane Glycoproteins ,Effector ,T-cell receptor ,Cell Differentiation ,RC581-607 ,Adoptive Transfer ,Cell biology ,Mice, Inbred C57BL ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,T cell differentiation ,Immunologic diseases. Allergy ,Immunologic Memory ,Memory T cell ,030215 immunology - Abstract
Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection.
- Published
- 2021
49. New Family Members of FG Repeat Proteins and Their Unexplored Roles During Phase Separation
- Author
-
Yoichi Shinkai, Takamitsu Miyafusa, and Masahiro Kuramochi
- Subjects
FG repeat ,QH301-705.5 ,Review ,Intrinsically disordered proteins ,Cell and Developmental Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,keratohyalin granule ,Biology (General) ,Nuclear pore ,Nuclear membrane ,030304 developmental biology ,0303 health sciences ,Nucleoplasm ,Chemistry ,Effector ,Activator (genetics) ,Cell Biology ,intrinsically disordered protein ,P granule ,Cell biology ,medicine.anatomical_structure ,nuclear pore ,Cytoplasm ,Nucleoporin ,phase separation ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
The condensation and compartmentalization of biomacromolecules in the cell are driven by the process of phase separation. The main effectors of phase separation are intrinsically disordered proteins, which include proteins with a phenylalanine-glycine (FG) repeat domain. Our understanding of the biological function of FG repeat proteins during phase separation has been mainly derived from recent research on a member of the nuclear pore complex proteins, nucleoporins containing FG repeat domain (FG-NUPs). FG-NUPs form meshwork structures by inter- and intra-molecular FG domain interactions, which confine the nucleo-cytoplasmic exchange. Whereas FG-NUPs localize in the nuclear membrane, other FG repeat proteins reside in the cytoplasm and the nucleoplasm, and the biological function of the FG repeat domain of these proteins is not well described. In the present review, we list the FG repeat proteins that are known to phase separate in the cell, and review their biological functions. We extract the unraveled features of FG repeat proteins as an activator of barrier formation and homotypic cell-cell interactions. Understanding the regulatory mechanisms of FG repeat proteins will provide a potential delivery tool for therapeutic reagents.
- Published
- 2021
50. IL-10-Dependent Amelioration of Chronic Inflammatory Disease by Microdose Subcutaneous Delivery of a Prototypic Immunoregulatory Small Molecule
- Author
-
Jorge H. Tabares-Guevara, Julio C. Jaramillo, Laura Ospina-Quintero, Christian A. Piedrahíta-Ochoa, Natalia García-Valencia, David E. Bautista-Erazo, Erika Caro-Gómez, Camila Covián, Angello Retamal-Díaz, Luisa F. Duarte, Pablo A. González, Susan M. Bueno, Claudia A. Riedel, Alexis M. Kalergis, and José R. Ramírez-Pineda
- Subjects
0301 basic medicine ,Curcumin ,medicine.medical_treatment ,Immunology ,experimental autoimmune encephalomyelitis ,Inflammation ,Pharmacology ,Neuroprotection ,Immunomodulating Agents ,Mice ,03 medical and health sciences ,Apolipoproteins E ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Immunology and Allergy ,Original Research ,business.industry ,Effector ,immune regulation ,Experimental autoimmune encephalomyelitis ,FOXP3 ,chronic inflammatory disease ,RC581-607 ,Atherosclerosis ,medicine.disease ,Lipids ,Interleukin-10 ,Mice, Inbred C57BL ,Interleukin 10 ,030104 developmental biology ,Cytokine ,Chronic Disease ,Immunologic diseases. Allergy ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
One of the interventional strategies to reestablish the immune effector/regulatory balance, that is typically altered in chronic inflammatory diseases (CID), is the reinforcement of endogenous immunomodulatory pathways as the one triggered by interleukin (IL)-10. In a recent work, we demonstrated that the subcutaneous (sc) administration of an IL-10/Treg-inducing small molecule-based formulation, using a repetitive microdose (REMID) treatment strategy to preferentially direct the effects to the regional immune system, delays the progression of atherosclerosis. Here we investigated whether the same approach using other IL-10-inducing small molecule, such as the safe, inexpensive, and widely available polyphenol curcumin, could induce a similar protective effect in two different CID models. We found that, in apolipoprotein E deficient mice, sc treatment with curcumin following the REMID strategy induced atheroprotection that was not consequence of its direct systemic lipid-modifying or antioxidant activity, but instead paralleled immunomodulatory effects, such as reduced proatherogenic IFNγ/TNFα-producing cells and increased atheroprotective FOXP3+Tregs and IL-10-producing dendritic and B cells. Remarkably, when a similar strategy was used in the neuroinflammatory model of experimental autoimmune encephalomyelitis (EAE), significant clinical and histopathological protective effects were evidenced, and these were related to an improved effector/regulatory cytokine balance in restimulated splenocytes. The essential role of curcumin-induced IL-10 for neuroprotection was confirmed by the complete abrogation of the clinical effects in IL-10-deficient mice. Finally, the translational therapeutic prospection of this strategy was evidenced by the neuroprotection observed in mice starting the treatment one week after disease triggering. Collectively, results demonstrate the power of a simple natural IL-10-inducing small molecule to tackle chronic inflammation, when its classical systemic and direct pharmacological view is shifted towards the targeting of regional immune cells, in order to rationally harness its immunopharmacological potential. This shift implies that many well-known IL-10-inducing small molecules could be easily reformulated and repurposed to develop safe, innovative, and accessible immune-based interventions for CID.
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.