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Background: Dogs are definitive hosts of Echinococcus granulosus , with the small intestine being the only site of parasitic infections. However, the immunomodulatory processes that occur during interactions between E. granulosus and its definitive host remain unclear. Therefore, this study aimed to evaluate gene transcription patterns in canine small intestinal epithelial cells (CIECs) following stimulation by E. granulosus protoscoleces (PSCs). Particularly, this study investigated the roles of pattern recognition receptors (PRRs), involved in recognizing pathogen-associated molecular patterns (PAMPs) and mediating the host innate immune response to the tapeworm E. granulosus. Methods: RNA sequencing (RNA-seq) was used to examine gene transcription patterns in CIECs following stimulation with PSCs for 12 and 24 h. The potential roles of differentially expressed (DE) genes were inferred through Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: RNA-seq analysis identified 78,206,492–90,548,214 clean reads in 12 RNA samples. This included six samples stimulated with PSCs for 12 h (PSC1_12h–PSC3_12h) and 24 h (PSC1_24h–PSC3_24h) and six corresponding control samples (PBS1_12h–PBS3_12h and PBS1_24h–PBS3_24h). In the PSC_12h vs. PBS_12h and PSC_24h vs. PBS_24h groups, 3,520 (2,359 upregulated and 1,161 downregulated) and 3,287 (1765 upregulated and 1,522 downregulated) DEgenes were identified, respectively. The expression of 45 PRRs genes was upregulated in the PSC_12h and PSC_24h groups compared to those in the control groups, including 4 Toll-like receptors (TLRs), 4C-type lectin receptors (CLRs), 3 NOD-like receptors (NLRs), 17 G protein-coupled receptors (GPCRs), 4 scavenger receptors (SRs), and 13 leucine-rich repeat-containing proteins (LRRCs). GO enrichment and KEGG analyses revealed that these DEgenes were mainly involved in the regulation of host immune response processes and molecules. These included antigen processing and presentation, Th17, PI3K-Akt, Th1, and Th2 cell differentiation, neutrophil extracellular trap formation, NOD- and Toll-like receptors, TNF, intestinal immune network for IgA production and IL-17 signaling pathway. Furthermore, the identified DEgenes were involved in the regulation of signaling molecules and interaction (e.g., cell adhesion molecules and ECM-receptor interaction). Conclusion: These preliminary findings provide novel perspectives on the host innate immune response to E. granulosus PSC stimulation, with a focus on the involvement of E. granulosus -specific PRRs in host defense mechanisms against infection. [ABSTRACT FROM AUTHOR]

Periodontal disease remains a significant global health concern, characterized by complex host–pathogen interactions leading to tissue destruction. This review explored the role of pattern recognition receptors (PRRs) in the pathogenesis of periodontal disease, synthesizing current knowledge on their molecular mechanisms and potential as therapeutic targets. We examined the diverse family of PRRs, focusing on toll-like receptors (TLRs) and NOD-like receptors (NLRs), elucidating their activation by periodontal pathogens and subsequent downstream signaling cascades. This review highlights the intricate interplay between PRR-mediated pathways, including NF-κB and MAPK signaling, and their impact on inflammatory responses and bone metabolism in periodontal tissues. We discussed the emerging concept of PRR crosstalk and its implications for periodontal homeostasis and disease progression. Furthermore, this review addressed the potential of PRR-targeted therapies, exploring both challenges and opportunities in translating molecular insights into clinical applications. By providing an overview of PRRs in periodontal health and disease, this review aims to stimulate future research directions and inform the development of novel diagnostic and therapeutic strategies in periodontology. [ABSTRACT FROM AUTHOR]

Quantitative transcriptomics offers a new way to obtain a detailed picture of freshly isolated cells. By direct isolation, the cells are unaffected by in vitro culture, and the isolation at cold temperatures maintains the cells relatively unaltered in phenotype by avoiding activation through receptor cross-linking or plastic adherence. Simultaneous analysis of several cell types provides the opportunity to obtain detailed pictures of transcriptomic differences between them. Here, we present such an analysis focusing on four human blood cell populations and compare those to isolated human skin mast cells. Pure CD19+ peripheral blood B cells, CD14+ monocytes, and CD4+ and CD8+ T cells were obtained by fluorescence-activated cell sorting, and KIT+ human connective tissue mast cells (MCs) were purified by MACS sorting from healthy skin. Detailed information concerning expression levels of the different granule proteases, protease inhibitors, Fc receptors, other receptors, transcription factors, cell signaling components, cytoskeletal proteins, and many other protein families relevant to the functions of these cells were obtained and comprehensively discussed. The MC granule proteases were found exclusively in the MC samples, and the T-cell granzymes in the T cells, of which several were present in both CD4+ and CD8+ T cells. High levels of CD4 were also observed in MCs and monocytes. We found a large variation between the different cell populations in the expression of Fc receptors, as well as for lipid mediators, proteoglycan synthesis enzymes, cytokines, cytokine receptors, and transcription factors. This detailed quantitative comparative analysis of more than 780 proteins of importance for the function of these populations can now serve as a good reference material for research into how these entities shape the role of these cells in immunity and tissue homeostasis. [ABSTRACT FROM AUTHOR]

Innate immunity is the first line of defense against infections and the only known available strategy for invertebrates. Crustaceans, being mostly aquatic invertebrates, are constantly exposed to potential pathogens in the surrounding water. Their immune system abolishes most microbes that enter and are recognized as a threat. However, the stress produced by high population densities and abiotic changes, in aquaculture, disrupts the host-pathogen balance, leading to severe economic losses in this industry. Consequently, crustacean immunology has become a prime area of research where significant progress has been made. This review provides our current understanding of the key pattern recognition receptors in crustaceans, with special focus on Decapoda, and their roles in triggering an immune response. We discuss recent developments in the field of signal transduction pathways such as Toll-like receptors (TLRs) and the immune deficiency (IMD) pathway, and examine the role of antimicrobial peptides (AMPs) in pathogen defense. Additionally, we analyze how environmental stressors—such as temperature fluctuations, ammonia levels, and pollution—impact immune responses and increase susceptibility to diseases. Finally, we highlight future research directions, emphasizing the need to explore the interactions between environmental stressors and immune signaling pathways and to develop strategies to enhance immune responses in crustaceans within aquaculture settings. Altogether, these advancements deepen our understanding of pathogen recognition in invertebrates and the specific defense mechanisms employed by crustaceans, particularly in response to infections triggered by pathogens under abiotic stressors. [ABSTRACT FROM AUTHOR]

Receptor-like proteins (RLPs) are crucial pattern-recognition receptors on the surface of plant cells, which are involved in almost all processes of the plant life cycle. Recently, the evolution of high-throughput sequencing technology has strengthened the appraisal and identification of increasing numbers of RLPs and has primarily improved our understanding of the roles of RLPs in various biological processes. Here, we review the classification and evolutionary characteristics of RLPs and their regulatory roles in pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). In particular, we summarize the ligands recognized by RLPs, their co-receptors, and downstream signalling cascades mediated by RLPs. To summarize, this review offers beneficial guidance for researchers in at-a-glance comprehension of the function of RLPs. It also puts forward the prospect of mining broad-spectrum candidate genes in light of the research on the disease resistance mechanism of RLPs and current challenges in disease resistance breeding. [ABSTRACT FROM AUTHOR]

Dectin‐1 is a C‐type lectin‐receptor involved in sensing fungi by innate immune cells. Encoded by the Clec7a gene, Dectin‐1 exists in two major splice isoforms, Dectin‐1a and 1b, which differ in the presence of a membrane‐proximal stalk domain. As reported previously, this domain determines degradative routes for Dectin‐1a and 1b leading to the generation of a stable N‐terminal fragment exclusively from Dectin‐1a. Here, we narrow down the responsible part of the stalk and demonstrate the stabilisation of the Dectin‐1a N‐terminal fragment in tetraspanin‐enriched microdomains. C57BL/6 and BALB/c mice show divergent Dectin‐1 isoform expression patterns, which are caused by a single nucleotide polymorphism in exon 3 of the Clec7a gene, leading to a non‐sense Dectin‐1a mRNA in C57BL/6 mice. Using backcrossing, we generated mice with the C57BL/6 Clec7a allele on a BALB/c background and compared these to the parental strains. Expression of the C57BL/6 allele leads to the exclusive presence of the Dectin‐1b protein. Furthermore, it was associated with higher Dectin‐1 mRNA expression, but less Dectin‐1 at the cell surface according to flow cytometry. In neutrophils, this altered ROS production induced by Dectin‐1 model ligands, while cellular responses in macrophages and dendritic cells were not significantly influenced by the Dectin‐1 isoform pattern. [ABSTRACT FROM AUTHOR]

Background: Irritable bowel syndrome is a functional gastrointestinal disease of unknown etiology. Researchers have recently drawn attention to the possible role of viruses in the development of IBS and provided evidence in this regard. In this study, it was decided to investigate the possible role of rotavirus infection in the onset of IBS.Methods: Stool and serum samples were collected from 40 patients with IBS and 40 healthy individuals. To evaluate the previous exposure to rotavirus we checked the presence and concentration of anti-rotavirus IgG by ELISA. ELISA test was performed on the serum samples. Real-time PCR test was also used to measure the viral load in the stool. Finally, the data were analyzed by SPSS-22 software.Results: No significant relationship was found between anti-rotavirus IgG presence and Level in the serum of case and healthy individuals (p-value > 0.05) . Moreover, there was no significant difference between the viral genome load in the stool samples of the two groups (p-value > 0.05).Conclusion: According to the results, it seems unlikely that a link exists between rotavirus infection and the onset of irritable bowel syndrome, but the possible role of other gastrointestinal viruses, including coronavirus, remains.

Abstract Receptor-like proteins (RLPs) are crucial pattern-recognition receptors on the surface of plant cells, which are involved in almost all processes of the plant life cycle. Recently, the evolution of high-throughput sequencing technology has strengthened the appraisal and identification of increasing numbers of RLPs and has primarily improved our understanding of the roles of RLPs in various biological processes. Here, we review the classification and evolutionary characteristics of RLPs and their regulatory roles in pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). In particular, we summarize the ligands recognized by RLPs, their co-receptors, and downstream signalling cascades mediated by RLPs. To summarize, this review offers beneficial guidance for researchers in at-a-glance comprehension of the function of RLPs. It also puts forward the prospect of mining broad-spectrum candidate genes in light of the research on the disease resistance mechanism of RLPs and current challenges in disease resistance breeding.

Abstract Background Enterotoxigenic Escherichia coli (E. coli) is a threat to humans and animals that causes intestinal disorders. Antimicrobial resistance has urged alternatives, including Lactobacillus postbiotics, to mitigate the effects of enterotoxigenic E. coli. Methods Forty-eight newly weaned pigs were allotted to NC: no challenge/no supplement; PC: F18+ E. coli challenge/no supplement; ATB: F18+ E. coli challenge/bacitracin; and LPB: F18+ E. coli challenge/postbiotics and fed diets for 28 d. On d 7, pigs were orally inoculated with F18+ E. coli. At d 28, the mucosa-associated microbiota, immune and oxidative stress status, intestinal morphology, the gene expression of pattern recognition receptors (PRR), and intestinal barrier function were measured. Data were analyzed using the MIXED procedure in SAS 9.4. Results PC increased (P

Abstract Viral infections pose significant threats to human health, leading to a diverse spectrum of infectious diseases. The innate immune system serves as the primary barrier against viruses and bacteria in the early stages of infection. A rapid and forceful antiviral innate immune response is triggered by distinguishing between self-nucleic acids and viral nucleic acids. RNA-binding proteins (RBPs) are a diverse group of proteins which contain specific structural motifs or domains for binding RNA molecules. In the last decade, numerous of studies have outlined that RBPs influence viral replication via diverse mechanisms, directly recognizing viral nucleic acids and modulating the activity of pattern recognition receptors (PRRs). In this review, we summarize the functions of RBPs in regulation of host-virus interplay by controlling the activation of PRRs, such as RIG-I, MDA5, cGAS and TLR3. RBPs are instrumental in facilitating the identification of viral RNA or DNA, as well as viral structural proteins within the cellular cytoplasm and nucleus, functioning as co-receptor elements. On the other hand, RBPs are capable of orchestrating the activation of PRRs and facilitating the transmission of antiviral signals to downstream adaptor proteins by post-translational modifications or aggregation. Gaining a deeper comprehension of the interaction between the host and viruses is crucial for the development of novel therapeutics targeting viral infections.

Cutaneous hypersensitivity reactions (CHRs) are complex inflammatory skin disorders that affect humans and dogs. This study examined the inflammatory and immune responses leading to skin damage, inflammation, and irritation by investigating gene expression through quantitative PCR (qPCR) and protein localization through the immunohistochemistry (IHC) of specific receptors and molecules involved in CHRs. Formalin-fixed paraffin-embedded (FFPE) samples from canine CHR skin (n = 20) and healthy dog skin (n = 3) were analyzed for expression levels of eight genes, including members of the pattern recognition receptor (PRR) family, CD209 and CLEC4G, the Regakine-1-like chemokine, and acute phase proteins (APPs), LBP-like and Hp-like genes. Additionally, we examined the local involvement of IL-6, Janus Kinase 1 (JAK1), and the signal transducer activator of transcription 3 (STAT3) in the CHR cases. The study demonstrated statistically significant increases in the expression levels of CD209, Hp-like (p < 0.01), LBP-like, Regakine-1-like, and CLEC4G (p < 0.05) genes in CHRs compared to healthy controls. Conversely, IL-6, JAK1, and STAT3 showed no significant difference between the two groups (p > 0.05). Protein analysis revealed JAK1 and STAT3 expression in CHR hyperplastic epithelial cells, dermal fibroblasts, and endothelial cells of small capillaries, indicating a possible involvement in the JAK/STAT pathway in local inflammatory response regulation. Our findings suggest that the skin plays a role in the development of CHRs.

Background: Enterotoxigenic Escherichia coli (E. coli) is a threat to humans and animals that causes intestinal disorders. Antimicrobial resistance has urged alternatives, including Lactobacillus postbiotics, to mitigate the effects of enterotoxigenic E. coli. Methods: Forty-eight newly weaned pigs were allotted to NC: no challenge/no supplement; PC: F18+ E. coli challenge/no supplement; ATB: F18+ E. coli challenge/bacitracin; and LPB: F18+ E. coli challenge/postbiotics and fed diets for 28 d. On d 7, pigs were orally inoculated with F18+ E. coli. At d 28, the mucosa-associated microbiota, immune and oxidative stress status, intestinal morphology, the gene expression of pattern recognition receptors (PRR), and intestinal barrier function were measured. Data were analyzed using the MIXED procedure in SAS 9.4. Results: PC increased (P < 0.05) Helicobacter mastomyrinus whereas reduced (P < 0.05) Prevotella copri and P. stercorea compared to NC. The LPB increased (P < 0.05) P. stercorea and Dialister succinatiphilus compared with PC. The ATB increased (P < 0.05) Propionibacterium acnes, Corynebacterium glutamicum, and Sphingomonas pseudosanguinis compared to PC. The PC tended to reduce (P = 0.054) PGLYRP4 and increased (P < 0.05) TLR4, CD14, MDA, and crypt cell proliferation compared with NC. The ATB reduced (P < 0.05) NOD1 compared with PC. The LPB increased (P < 0.05) PGLYRP4, and interferon-γ and reduced (P < 0.05) NOD1 compared with PC. The ATB and LPB reduced (P < 0.05) TNF-α and MDA compared with PC. Conclusions: The F18+ E. coli challenge compromised intestinal health. Bacitracin increased beneficial bacteria showing a trend towards increasing the intestinal barrier function, possibly by reducing the expression of PRR genes. Lactobacillus postbiotics enhanced the immunocompetence of nursery pigs by increasing the expression of interferon-γ and PGLYRP4, and by reducing TLR4, NOD1, and CD14. [ABSTRACT FROM AUTHOR]

Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, Toll‐like Receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1′‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1′)βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation. [ABSTRACT FROM AUTHOR]

Viral infections pose significant threats to human health, leading to a diverse spectrum of infectious diseases. The innate immune system serves as the primary barrier against viruses and bacteria in the early stages of infection. A rapid and forceful antiviral innate immune response is triggered by distinguishing between self-nucleic acids and viral nucleic acids. RNA-binding proteins (RBPs) are a diverse group of proteins which contain specific structural motifs or domains for binding RNA molecules. In the last decade, numerous of studies have outlined that RBPs influence viral replication via diverse mechanisms, directly recognizing viral nucleic acids and modulating the activity of pattern recognition receptors (PRRs). In this review, we summarize the functions of RBPs in regulation of host-virus interplay by controlling the activation of PRRs, such as RIG-I, MDA5, cGAS and TLR3. RBPs are instrumental in facilitating the identification of viral RNA or DNA, as well as viral structural proteins within the cellular cytoplasm and nucleus, functioning as co-receptor elements. On the other hand, RBPs are capable of orchestrating the activation of PRRs and facilitating the transmission of antiviral signals to downstream adaptor proteins by post-translational modifications or aggregation. Gaining a deeper comprehension of the interaction between the host and viruses is crucial for the development of novel therapeutics targeting viral infections. [ABSTRACT FROM AUTHOR]

Introduction: Adjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. Bordetella colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates TH1/TH17-polarized immune responses to protein antigens from Bordetella pertussis and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a TH2 response. Methods: To understand the mechanism of BcfA-driven TH1/TH17 vs. TH2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs. Results: PRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an in vitro TH cell polarization system, we found that BcfA-stimulated BMDC supernatant supported TFH and TH1 while suppressing TH2 gene programming. Conclusions: Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses. [ABSTRACT FROM AUTHOR]

Acanthamoeba, are ubiquitous eukaryotic microorganisms, that play a pivotal role in recognizing and engulfing various microbes during predation, offering insights into microbial dynamics and immune responses. An intriguing observation lies in the apparent preference of Acanthamoeba for Gram-negative over Gram-positive bacteria, suggesting potential differences in the recognition and response mechanisms to bacterial prey. Here, we comprehensively review pattern recognition receptors (PRRs) and microbe associated molecular patterns (MAMPs) that influence Acanthamoeba interactions with bacteria. We analyze the molecular mechanisms underlying these interactions, and the key finding of this review is that Acanthamoeba exhibits an affinity for bacterial cell surface appendages that are decorated with carbohydrates. Notably, this parallels warm-blooded immune cells, underscoring a conserved evolutionary strategy in microbial recognition. This review aims to serve as a foundation for exploring PRRs and MAMPs. These insights enhance our understanding of ecological and evolutionary dynamics in microbial interactions and shed light on fundamental principles governing immune responses. Leveraging Acanthamoeba as a model organism, provides a bridge between ecological interactions and immunology, offering valuable perspectives for future research. [ABSTRACT FROM AUTHOR]

Insects are known to dominate adverse ecological conditions due to their diverse adaptations and resilient biological traits, with their immune systems playing a crucial role in this dominance. Traditionally, insects were thought to lack adaptive immune responses due to their inability to produce antibodies and transfer immunity across generations. However, recent research using insects as model organisms has challenged this notion, revealing that prior exposure to sublethal doses of pathogens or pathogen‐derived materials can protect against subsequent lethal exposures—a phenomenon known as ‘immune priming’. Evidence of bacterial, fungal and viral immune priming across different insect species highlights various types of priming, including trans‐stadial (across life stages) and trans‐generational (across generations) priming. Despite differing views on immune priming, its potential applications in agriculture are considerable, especially in biological control, the utilization of beneficial insects and sustainable pest management. This review explores the intricate dynamics of immune priming in insects, comparing it to vertebrate immunity and investigates its mechanisms, potential agricultural applications and future prospects. [ABSTRACT FROM AUTHOR]

Phytophthora cinnamomi Rands devastates forest species worldwide, causing significant ecological and economic impacts. The European chestnut (Castanea sativa) is susceptible to this hemibiotrophic oomycete, whereas the Asian chestnuts (Castanea crenata and Castanea mollissima) are resistant and have been successfully used as resistance donors in breeding programs. The molecular mechanisms underlying the different disease outcomes among chestnut species are a key foundation for developing science-based control strategies. However, these are still poorly understood. Dual RNA sequencing was performed in C. sativa and C. crenata roots inoculated with P. cinnamomi. The studied time points represent the pathogen's hemibiotrophic lifestyle previously described at the cellular level. Phytophthora cinnamomi expressed several genes related to pathogenicity in both chestnut species, such as cell wall-degrading enzymes, host nutrient uptake transporters, and effectors. However, the expression of effectors related to the modulation of host programmed cell death (elicitins and NLPs) and sporulation-related genes was higher in the susceptible chestnut. After pathogen inoculation, 1,556 and 488 genes were differentially expressed by C. crenata and C. sativa, respectively. The most significant transcriptional changes occur at 2 h after inoculation (hai) in C. sativa and 48 hai in C. crenata. Nevertheless, C. crenata induced more defense-related genes, indicating that the resistant response to P. cinnamomi is controlled by multiple loci, including several pattern recognition receptors, genes involved in the phenylpropanoid, salicylic acid and ethylene/jasmonic acid pathways, and antifungal genes. Importantly, these results validate previously observed cellular responses for C. crenata. Collectively, this study provides a comprehensive time-resolved description of the chestnut-P. cinnamomi dynamic, revealing new insights into susceptible and resistant host responses and important pathogen strategies involved in disease development. [ABSTRACT FROM AUTHOR]

We previously showed that several polymorphisms in genes encoding pattern recognition receptors that cause amino acid substitutions alter pathogen recognition ability and disease susceptibility in pigs. In this study, we expanded our analysis to a wide range of immune-related genes and investigated polymorphism distribution and its influence on pneumonia in multiple commercial pig populations. Among the polymorphisms in 42 genes causing 634 amino acid substitutions extracted from the swine genome database, 80 in 24 genes were found to have a minor allele frequency of at least 10% in Japanese breeding stock pigs via targeted resequencing. Of these, 62 single nucleotide polymorphisms (SNPs) in 23 genes were successfully genotyped in 862 pigs belonging to four populations with data on pneumonia severity. Association analysis using a generalized linear mixed model revealed that 12 SNPs in nine genes were associated with pneumonia severity. In particular, SNPs in the cellular receptor for immunoglobulin G FCGR2B and the intracellular nucleic acid sensors IFI16 and LRRFIP1 were found to be associated with mycoplasmal pneumonia of swine or porcine pleuropneumonia in multiple populations and may therefore have wide applications in the improvement of disease resistance in pigs. Functional analyses at the cellular and animal levels are required to clarify the mechanisms underlying the effects of these SNPs on disease susceptibility. [ABSTRACT FROM AUTHOR]

Periodontitis is one of the chronic diseases that have the greatest impact on human health, and it is associated with several other chronic diseases. Tissue damage associated with periodontitis is often connected with immune response. Immune cells are a crucial component of the human immune system and are directly involved in periodontitis during the inflammatory phase of the disease. Macrophages, as a key component of the immune system, are responsible for defence, antigen presentation and phagocytosis in healthy tissue. They are also closely linked to the development and resolution of periodontitis, through mechanisms such as macrophage polarization, pattern recognition receptors recognition, efferocytosis, and Specialized Pro-resolving Mediators (SPMs) production. Additionally, apoptosis and autophagy are also known to play a role in the recovery of periodontitis. This review aims to investigate the aforementioned mechanisms in more detail and identify novel therapeutic approaches for periodontitis.

ABSTRACTVaccines are an effective way to prevent the emergence and spread of antibiotic resistance by preventing diseases and establishing herd immunity. However, the reduced effectiveness of vaccines in the elderly due to immunosenescence is one of the significant contributors to the increasing antibiotic resistance. To counteract this decline and enhance vaccine effectiveness in the elderly, adjuvants play a pivotal role. Adjuvants are designed to augment the effectiveness of vaccines by activating the innate immune system, particularly through pattern recognition receptors on antigen-presenting cells. To improve vaccine effectiveness in the elderly using adjuvants, it is imperative to select the appropriate adjuvants based on an understanding of immunosenescence and the mechanisms of adjuvant functions. This review demonstrates the phenomenon of immunosenescence and explores various types of adjuvants, including their mechanisms and their potential in improving vaccine effectiveness for the elderly, thereby contributing to developing more effective vaccines for this vulnerable demographic.

BackgroundDogs are definitive hosts of Echinococcus granulosus, with the small intestine being the only site of parasitic infections. However, the immunomodulatory processes that occur during interactions between E. granulosus and its definitive host remain unclear. Therefore, this study aimed to evaluate gene transcription patterns in canine small intestinal epithelial cells (CIECs) following stimulation by E. granulosus protoscoleces (PSCs). Particularly, this study investigated the roles of pattern recognition receptors (PRRs), involved in recognizing pathogen-associated molecular patterns (PAMPs) and mediating the host innate immune response to the tapeworm E. granulosus.MethodsRNA sequencing (RNA-seq) was used to examine gene transcription patterns in CIECs following stimulation with PSCs for 12 and 24 h. The potential roles of differentially expressed (DE) genes were inferred through Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses.ResultsRNA-seq analysis identified 78,206,492–90,548,214 clean reads in 12 RNA samples. This included six samples stimulated with PSCs for 12 h (PSC1_12h–PSC3_12h) and 24 h (PSC1_24h–PSC3_24h) and six corresponding control samples (PBS1_12h–PBS3_12h and PBS1_24h–PBS3_24h). In the PSC_12h vs. PBS_12h and PSC_24h vs. PBS_24h groups, 3,520 (2,359 upregulated and 1,161 downregulated) and 3,287 (1765 upregulated and 1,522 downregulated) DEgenes were identified, respectively. The expression of 45 PRRs genes was upregulated in the PSC_12h and PSC_24h groups compared to those in the control groups, including 4 Toll-like receptors (TLRs), 4C-type lectin receptors (CLRs), 3 NOD-like receptors (NLRs), 17 G protein-coupled receptors (GPCRs), 4 scavenger receptors (SRs), and 13 leucine-rich repeat-containing proteins (LRRCs). GO enrichment and KEGG analyses revealed that these DEgenes were mainly involved in the regulation of host immune response processes and molecules. These included antigen processing and presentation, Th17, PI3K-Akt, Th1, and Th2 cell differentiation, neutrophil extracellular trap formation, NOD- and Toll-like receptors, TNF, intestinal immune network for IgA production and IL-17 signaling pathway. Furthermore, the identified DEgenes were involved in the regulation of signaling molecules and interaction (e.g., cell adhesion molecules and ECM-receptor interaction).ConclusionThese preliminary findings provide novel perspectives on the host innate immune response to E. granulosus PSC stimulation, with a focus on the involvement of E. granulosus-specific PRRs in host defense mechanisms against infection.

Innate immunity is the first line of defense against infections and the only known available strategy for invertebrates. Crustaceans, being mostly aquatic invertebrates, are constantly exposed to potential pathogens in the surrounding water. Their immune system abolishes most microbes that enter and are recognized as a threat. However, the stress produced by high population densities and abiotic changes, in aquaculture, disrupts the host-pathogen balance, leading to severe economic losses in this industry. Consequently, crustacean immunology has become a prime area of research where significant progress has been made. This review provides our current understanding of the key pattern recognition receptors in crustaceans, with special focus on Decapoda, and their roles in triggering an immune response. We discuss recent developments in the field of signal transduction pathways such as Toll-like receptors (TLRs) and the immune deficiency (IMD) pathway, and examine the role of antimicrobial peptides (AMPs) in pathogen defense. Additionally, we analyze how environmental stressors—such as temperature fluctuations, ammonia levels, and pollution—impact immune responses and increase susceptibility to diseases. Finally, we highlight future research directions, emphasizing the need to explore the interactions between environmental stressors and immune signaling pathways and to develop strategies to enhance immune responses in crustaceans within aquaculture settings. Altogether, these advancements deepen our understanding of pathogen recognition in invertebrates and the specific defense mechanisms employed by crustaceans, particularly in response to infections triggered by pathogens under abiotic stressors.

Jingjing Wang,1 Yirui Dong,1 Xuewei Zheng,1 Haodi Ma,1 Mengjiao Huang,1 Dongliao Fu,1 Jiangbo Liu,2 Qinan Yin1,3 1School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, People’s Republic of China; 2Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, People’s Republic of China; 3Henan Engineering Research Center of Digital Pathology and Artificial Intelligence Diagnosis, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, People’s Republic of ChinaCorrespondence: Qinan Yin, School of Medical Technology and Engineering, Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luoyang, People’s Republic of China, 471003, Email qinanyin@haust.edu.cn Jiangbo Liu, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Guanlin Avenue, Luoyang, 471031, People’s Republic of China, Email jiangboliuxing@163.comAbstract: Innate immunity is the first line of defense in the human body, and it plays an important role in defending against viral infection. Viruses are identified by different pattern-recognition receptors (PRRs) that activate the mitochondrial antiviral signaling protein (MAVS) or transmembrane protein 173 (STING), which trigger multiple signaling cascades that cause nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) to produce inflammatory factors and interferons (IFNs). PRRs play a pivotal role as the first step in pathogen induction of interferon production. Interferon elicits antiviral activity by inducing the transcription of hundreds of IFN-stimulated genes (ISGs) via the janus kinase (JAK) – signal transducer and activator of transcription (STAT) pathway. An increasing number of studies have shown that environmental, pathogen and host factors regulate the IFN signaling pathway. Here, we summarize the mechanisms of host factor modulation in IFN production via pattern recognition receptors. These regulatory mechanisms maintain interferon levels in a normal state and clear viruses without inducing autoimmune disease.Keywords: pattern recognition receptors, interferon-signaling pathway, host factors

The cyclic GMP–AMP synthase (cGAS), a prominent intracellular DNA sensor in mammalian cells, controls the innate immune response and the stimulator of interferon genes (STING)‐mediated synthesis of pro‐inflammatory cytokines, such as type‐I interferon (IFN‐I). For decades, IFN‐I has been hypothesized to be essential in the development of systemic lupus erythematosus (SLE), a chronic multisystem autoimmunity characterized by immune complex (IC) deposition in small vessels. Recent findings revealed that the activation of the cGAS–STING pathway by self‐DNA would propagate the autoimmune responses via upregulating IFN‐I production in SLE. In this review, we aimed to provide a comprehensive outlook of the role of the cGAS–STING pathway in SLE pathobiology, as well as, a better understanding of current therapeutic opportunities targeting this axis. [ABSTRACT FROM AUTHOR]

Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are understudied. The lung endothelium is located next to infected epithelial cells and bystander inflammation may contribute to thromboinflammation and COVID-19-associated coagulopathy. Here, we investigated age-associated SARS-CoV-2 pathogenesis and endothelial inflammatory responses using humanized K18-hACE2 mice. Survival was reduced to 20% in aged mice (85–112 weeks) versus 50% in young mice (12–15 weeks) at 10 days post infection (dpi). Bulk RNA-sequencing of endothelial cells from mock and infected mice at 2dpi of both age groups (aged: 72–85 weeks; young: 15 weeks) showed substantially lower significant differentially regulated genes in infected aged mice than in young mice (712 versus 2294 genes). Viral recognition and anti-viral pathways such as RIG-I-like receptor signaling, NOD-like receptor signaling and interferon signaling were regulated in response to SARS-CoV-2. Young mice showed several fold higher interferon responses (Ifitm3, Ifit1, Isg15, Stat1) and interferon-induced chemokines (Cxcl10 and Cxcl11) than aged mice. Endothelial cells from infected young mice displayed elevated expression of chemokines (Cxcl9, Ccl2) and leukocyte adhesion markers (Icam1) underscoring that inflammation of lung endothelium during infection could facilitate leukocyte adhesion and thromboinflammation. TREM1 and acute phase response signaling were particularly prominent in endothelial cells from infected young mice. Immunohistochemistry was unable to detect viral protein in pulmonary endothelium. In conclusion, our data demonstrate that the early host response of the endothelium to SARS-CoV-2 infection declines with aging, which could be a potential contributor to disease severity. [ABSTRACT FROM AUTHOR]

Constitutively active KRAS mutations are among the major drivers of lung cancer, yet the identity of molecular co‐operators of oncogenic KRAS in the lung remains ill‐defined. The innate immune cytosolic DNA sensor and pattern recognition receptor (PRR) Absent‐in‐melanoma 2 (AIM2) is best known for its assembly of multiprotein inflammasome complexes and promoting an inflammatory response. Here, we define a role for AIM2, independent of inflammasomes, in KRAS‐addicted lung adenocarcinoma (LAC). In genetically defined and experimentally induced (nicotine‐derived nitrosamine ketone; NNK) LAC mouse models harboring the KrasG12D driver mutation, AIM2 was highly upregulated compared with other cytosolic DNA sensors and inflammasome‐associated PRRs. Genetic ablation of AIM2 in KrasG12D and NNK‐induced LAC mouse models significantly reduced tumor growth, coincident with reduced cellular proliferation in the lung. Bone marrow chimeras suggest a requirement for AIM2 in KrasG12D‐driven LAC in both hematopoietic (immune) and non‐hematopoietic (epithelial) cellular compartments, which is supported by upregulated AIM2 expression in immune and epithelial cells of mutant KRAS lung tissues. Notably, protection against LAC in AIM2‐deficient mice is associated with unaltered protein levels of mature Caspase‐1 and IL‐1β inflammasome effectors. Moreover, genetic ablation of the key inflammasome adapter, ASC, did not suppress KrasG12D‐driven LAC. In support of these in vivo findings, AIM2, but not mature Caspase‐1, was upregulated in human LAC patient tumor biopsies. Collectively, our findings reveal that endogenous AIM2 plays a tumor‐promoting role, independent of inflammasomes, in mutant KRAS‐addicted LAC, and suggest innate immune DNA sensing may provide an avenue to explore new therapeutic strategies in lung cancer. [ABSTRACT FROM AUTHOR]

Enterococcus faecalis is an important contributor to the persistence of chronic apical periodontitis. However, the mechanism by which E. faecalis infection in the root canals and dentinal tubules affects periapical tissue remains unclear. Bacterial extracellular vesicles (EVs) act as natural carriers of microbe-associated molecular patterns (MAMPs) and have recently attracted considerable attention. In this study, we investigated the role of EVs derived from E. faecalis in the pathogenesis of apical periodontitis. We observed that E. faecalis EVs can induce inflammatory bone destruction in the periapical areas of mice. Double-labeling immunofluorescence indicated that M1 macrophage infiltration was increased by E. faecalis EVs in apical lesions. Moreover, in vitro experiments demonstrated the internalization of E. faecalis EVs into macrophages. Macrophages tended to polarize toward the M1 profile after treatment with E. faecalis EVs. Pattern recognition receptors (PRRs) can recognize MAMPs of bacterial EVs and, in turn, trigger inflammatory responses. Thus, we performed further mechanistic exploration, which showed that E. faecalis EVs considerably increased the expression of NOD2, a cytoplasmic PRR, and that inhibition of NOD2 markedly reduced macrophage M1 polarization induced by E. faecalis EVs. RIPK2 ubiquitination is a major downstream of NOD2. We also observed increased RIPK2 ubiquitination in macrophages treated with E. faecalis EVs, and E. faecalis EV-induced macrophage M1 polarization was notably alleviated by the RIPK2 ubiquitination inhibitor. Our study revealed the potential for EVs to be considered a virulence factor of E. faecalis and found that E. faecalis EVs can promote macrophage M1 polarization via NOD2/RIPK2 signaling. To our knowledge, this is the first report to investigate apical periodontitis development from the perspective of bacterial vesicles and demonstrate the role and mechanism of E. faecalis EVs in macrophage polarization. This study expands our understanding of the pathogenic mechanism of E. faecalis and provides novel insights into the pathogenesis of apical periodontitis. [ABSTRACT FROM AUTHOR]

Microglia directly sense neurotransmitters, including norepinephrine and γ-aminobutyric acid (GABA), which act as 'brain-associated molecular patterns' to shape neuronal connectivity. Cytokines can instruct distinct microglial functional states. Microglia contact different sites on neuronal bodies, from the dendrite to the soma to the axon, using activity-dependent mechanisms, including purinergic sensing via P2Y12. Microglia can transiently alter synaptic function by interposing between pre- and post-synaptic membranes; they can also alter synapse numbers by remodeling connections. Microglia (tissue-resident macrophages of the brain) dynamically regulate healthy brain function and connectivity by directly sensing molecular patterns associated with neuronal activity, which include neurotransmitters, purines, and portions of remodeling neural circuits. Microglia are brain-resident macrophages that play key roles in brain development and experience dependent plasticity. In this review we discuss recent findings regarding the molecular mechanisms through which mammalian microglia sense the unique molecular patterns of the homeostatic brain. We propose that microglial function is acutely controlled in response to 'brain-associated molecular patterns' (BAMPs) that function as indicators of neuronal activity and neural circuit remodeling. A further layer of regulation comes from instructive cytokine cues that define unique microglial functional states. A systematic investigation of the receptors and signaling pathways that mediate these two regulatory axes may begin to define a functional code for microglia–neuron interactions. [ABSTRACT FROM AUTHOR]

C-type lectins in organisms play an important role in the process of innate immunity. In this study, a C-type lectin belonging to the DC-SIGN class of Micropterus salmoides was identified. MsDC-SIGN is classified as a type II transmembrane protein. The extracellular segment of MsDC-SIGN possesses a coiled-coil region and a carbohydrate recognition domain (CRD). The key amino acid motifs of the extracellular CRD of MsDC-SIGN in Ca2+-binding site 2 were EPN (Glu-Pro-Asn) and WYD (Trp-Tyr-Asp). MsDC-SIGN-CRD can bind to four pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), glucan, peptidoglycan (PGN), and mannan. Moreover, it can also bind to Gram-positive, Gram-negative bacteria, and fungi. Its CRD can agglutinate microbes and displays D-mannose and D-galactose binding specificity. MsDC-SIGN was distributed in seven tissues of the largemouth bass, among which the highest expression was observed in the liver, followed by the spleen and intestine. Additionally, MsDC-SIGN was present on the membrane of M. salmoides leukocytes, thereby augmenting the phagocytic activity against bacteria. In a subsequent investigation, the expression patterns of the MsDC-SIGN gene and key genes associated with the TLR signaling pathway (TLR4, NF-κB, and IL10) exhibited an up-regulated expression response to the stimulation of Aeromonas hydrophila. Furthermore, through RNA interference of MsDC-SIGN, the expression level of the DC-SIGN signaling pathway-related gene (RAF1) and key genes associated with the TLR signaling pathway (TLR4, NF-κB, and IL10) was decreased. Therefore, MsDC-SIGN plays a pivotal role in the immune defense against A. hydrophila by modulating the TLR signaling pathway. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment that utilizes viruses to preferentially infect and eliminate cancer cells while stimulating the immune response. In this review, we synthesize the current literature on the molecular circuits of immune sensing and response to oncolytic virotherapy, focusing on viral DNA or RNA sensing by infected cells, cytokine and danger-associated-signal sensing by neighboring cells, and the subsequent downstream activation of immune pathways. These sequential sense-and-response mechanisms involve the triggering of molecular sensors by viruses or infected cells to activate transcription factors and related genes for a breadth of immune responses. We describe how the molecular signals induced in the tumor upon virotherapy can trigger diverse immune signaling pathways, activating both antigen-presenting-cell-based innate and T cell-based adaptive immune responses. Insights into these complex mechanisms provide valuable knowledge for enhancing oncolytic virotherapy strategies. [ABSTRACT FROM AUTHOR]

Bacillus pumilus TUAT1 acts as plant growth–promoting rhizobacteria for various plants like rice and Arabidopsis. Under stress conditions, B. pumilus TUAT1 forms spores with a thick peptidoglycan (PGN) cell wall. Previous research showed that spores were significantly more effective than vegetative cells in enhancing plant growth. In Arabidopsis , lysin motif proteins, LYM1, LYM3 and CERK1, are required for recognizing bacterial PGNs to mediate immunity. Here, we examined the involvement of PGN receptor proteins in the plant growth promotion (PGP) effects of B. pumilus TUAT1 using Arabidopsis mutants defective in PGN receptors. Root growth of wild-type (WT), cerk1-1, lym1-1 and lym1-2 mutant plants was significantly increased by TUAT1 inoculation, but this was not the case for lym3-1 and lym3-2 mutant plants. RNA-seq analysis revealed that the expression of a number of defense-related genes was upregulated in lym3 mutant plants. These results suggested that B. pumilus TUAT1 may act to reduce the defense response, which is dependent on a functional LYM3. The expression of the defense-responsive gene, WRKY29 , was significantly induced by the elicitor flg-22, in both WT and lym3 mutant plants, while this induction was significantly reduced by treatment with B. pumilus TUAT1 and PGNs in WT, but not in lym3 mutant plants. These findings suggest that the PGNs of B. pumilus TUAT1 may be recognized by the LYM3 receptor protein, suppressing the defense response, which results in plant growth promotion in a trade-off between defense and growth. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders denote a broad range of illnesses involving neurology and psychiatry. These disorders include depressive disorders, anxiety, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorders, headaches, and epilepsy. In addition to their main neuropathology that lies in the central nervous system (CNS), lately, studies have highlighted the role of immunity and neuroinflammation in neuropsychiatric disorders. Toll‐like receptors (TLRs) are innate receptors that act as a bridge between the innate and adaptive immune systems via adaptor proteins (e.g., MYD88) and downstream elements; TLRs are classified into 13 families that are involved in normal function and illnesses of the CNS. TLRs expression affects the course of neuropsychiatric disorders, and is influenced during their pharmacotherapy; For example, the expression of multiple TLRs is normalized during the major depressive disorder pharmacotherapy. Here, the role of TLRs in neuroimmunology, treatment, and management of neuropsychiatric disorders is discussed. We recommend longitudinal studies to comparatively assess the cell‐type‐specific expression of TLRs during treatment, illness progression, and remission. Also, further research should explore molecular insights into TLRs regulation and related pathways. [ABSTRACT FROM AUTHOR]

The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape life’s evolution. During this process, the interactions between viral receptors and viruses have garnered significant interest since viral receptors are cell surface proteins exploited by viruses to initiate infection. Our study sheds light on the arms race between the MDA5 receptor and 5’ppp-RNA virus in a lower vertebrate fish, Miichthys miiuy. Firstly, the frequent and independent loss events of RIG-I in vertebrates prompted us to search for alternative immune substitutes, with homology-dependent genetic compensation response (HDGCR) being the main pathway. Our further analysis suggested that MDA5 of M. miiuy and Gallus gallus, the homolog of RIG-I, can replace RIG-I in recognizing 5’ppp-RNA virus, which may lead to redundancy of RIG-I and loss from the species genome during evolution. Secondly, as an adversarial strategy, 5’ppp-RNA SCRV can utilize the m6A methylation mechanism to degrade MDA5 and weaken its antiviral immune ability, thus promoting its own replication and immune evasion. In summary, our study provides a snapshot into the interaction and coevolution between vertebrate and virus, offering valuable perspectives on the ecological and evolutionary factors that contribute to the diversity of the immune system.

IntroductionAdjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. Bordetella colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates TH1/TH17-polarized immune responses to protein antigens from Bordetella pertussis and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a TH2 response.MethodsTo understand the mechanism of BcfA-driven TH1/TH17 vs. TH2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs.ResultsPRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an in vitro TH cell polarization system, we found that BcfA-stimulated BMDC supernatant supported TFH and TH1 while suppressing TH2 gene programming.ConclusionsOverall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.

Acanthamoeba, are ubiquitous eukaryotic microorganisms, that play a pivotal role in recognizing and engulfing various microbes during predation, offering insights into microbial dynamics and immune responses. An intriguing observation lies in the apparent preference of Acanthamoeba for Gram-negative over Gram-positive bacteria, suggesting potential differences in the recognition and response mechanisms to bacterial prey. Here, we comprehensively review pattern recognition receptors (PRRs) and microbe associated molecular patterns (MAMPs) that influence Acanthamoeba interactions with bacteria. We analyze the molecular mechanisms underlying these interactions, and the key finding of this review is that Acanthamoeba exhibits an affinity for bacterial cell surface appendages that are decorated with carbohydrates. Notably, this parallels warm-blooded immune cells, underscoring a conserved evolutionary strategy in microbial recognition. This review aims to serve as a foundation for exploring PRRs and MAMPs. These insights enhance our understanding of ecological and evolutionary dynamics in microbial interactions and shed light on fundamental principles governing immune responses. Leveraging Acanthamoeba as a model organism, provides a bridge between ecological interactions and immunology, offering valuable perspectives for future research.

Phytophthora cinnamomi Rands devastates forest species worldwide, causing significant ecological and economic impacts. The European chestnut (Castanea sativa) is susceptible to this hemibiotrophic oomycete, whereas the Asian chestnuts (Castanea crenata and Castanea mollissima) are resistant and have been successfully used as resistance donors in breeding programs. The molecular mechanisms underlying the different disease outcomes among chestnut species are a key foundation for developing science-based control strategies. However, these are still poorly understood. Dual RNA sequencing was performed in C. sativa and C. crenata roots inoculated with P. cinnamomi. The studied time points represent the pathogen’s hemibiotrophic lifestyle previously described at the cellular level. Phytophthora cinnamomi expressed several genes related to pathogenicity in both chestnut species, such as cell wall–degrading enzymes, host nutrient uptake transporters, and effectors. However, the expression of effectors related to the modulation of host programmed cell death (elicitins and NLPs) and sporulation-related genes was higher in the susceptible chestnut. After pathogen inoculation, 1,556 and 488 genes were differentially expressed by C. crenata and C. sativa, respectively. The most significant transcriptional changes occur at 2 h after inoculation (hai) in C. sativa and 48 hai in C. crenata. Nevertheless, C. crenata induced more defense-related genes, indicating that the resistant response to P. cinnamomi is controlled by multiple loci, including several pattern recognition receptors, genes involved in the phenylpropanoid, salicylic acid and ethylene/jasmonic acid pathways, and antifungal genes. Importantly, these results validate previously observed cellular responses for C. crenata. Collectively, this study provides a comprehensive time-resolved description of the chestnut–P. cinnamomi dynamic, revealing new insights into susceptible and resistant host responses and important pathogen strategies involved in disease development.

Recent research highlights that inflammatory signaling pathways such as pattern recognition receptor (PRR) signaling and inflammatory cytokine signaling play an important role in both on‐demand hematopoiesis as well as steady‐state hematopoiesis. Knockout studies have demonstrated the necessity of several distinct pathways in these processes, but often lack information about the contribution of specific cell types to the phenotypes in question. Transplantation studies have increased the resolution to the level of specific cell types by testing the necessity of inflammatory pathways specifically in donor hematopoietic stem and progenitor cells (HSPCs) or in recipient niche cells. Here, we argue that for an integrated understanding of how these processes occur in vivo and to inform the development of therapies that modulate hematopoietic responses, we need studies that knockout inflammatory signaling receptors in a cell‐specific manner and compare the phenotypes caused by knockout in individual niche cells versus HSPCs. [ABSTRACT FROM AUTHOR]

Koi herpesvirus (KHV, CyHV-3) causes severe economic losses in carp farms. Its eradication is challenging due to the establishment of latency in blood leukocytes and other tissues. To understand the molecular mechanisms leading to KHV infection in leukocytes, common carp were bath-exposed to KHV at 17 °C. After confirming the presence of viral transcripts in blood leukocytes at ten days post infection, RNA-Seq was performed on peripheral blood leukocytes on the Illumina NovaSeq. KHV infection triggered a robust immune response mediated by pattern recognition receptors, mainly toll-like receptors (tlr2, tlr5, tlr7, and tlr13), urokinase plasminogen activator surface receptor-like, galectin proteins, and lipid mediators such as leukotriene B4 receptor 1. Enriched pathways showed increased mitochondria oxidative phosphorylation and the activation of signalling pathways such as mitogen-activated protein kinases (MAPKs) and vascular endothelial growth factor (VEGF). KHV-infected leukocytes showed low production of reactive oxygen species (ROS) and glutathione metabolism, high iron export and phagocytosis activity, and low autophagy. Macrophage polarization was deduced from the up-regulation of genes such as arginase non-hepatic 1-like, macrophage mannose receptor-1, crem, il-10, and il-13 receptors, while markers for cytotoxic T cells were observed to be down-regulated. Further work is required to characterise these leukocyte subsets and the molecular events leading to KHV latency in blood leukocytes. [ABSTRACT FROM AUTHOR]

Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) capture pathogens and process antigens, playing a crucial role in activating naïve T cells, bridging the gap between innate and acquired immunity. However, little is known about DC activation when facing Leishmania parasites. Thus, this study investigates in vitro activity of canine peripheral blood-derived DCs (moDCs) exposed to L. infantum and L. amazonensis parasites and their extracellular vesicles (EVs). L. infantum increased toll-like receptor 4 gene expression in synergy with nuclear factor κB activation and the generation of pro-inflammatory cytokines. This parasite also induced the expression of class II molecules of major histocompatibility complex (MHC) and upregulated co-stimulatory molecule CD86, which, together with the release of chemokine CXCL16, can attract and help in T lymphocyte activation. In contrast, L. amazonensis induced moDCs to generate a mix of pro- and anti-inflammatory cytokines, indicating that this parasite can establish a different immune relationship with DCs. EVs promoted moDCs to express class I MHC associated with the upregulation of co-stimulatory molecules and the release of CXCL16, suggesting that EVs can modulate moDCs to attract cytotoxic CD8+ T cells. Thus, these parasites and their EVs can shape DC activation. A detailed understanding of DC activation may open new avenues for the development of advanced leishmaniasis control strategies. [ABSTRACT FROM AUTHOR]

Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are understudied. The lung endothelium is located next to infected epithelial cells and bystander inflammation may contribute to thromboinflammation and COVID-19-associated coagulopathy. Here, we investigated age-associated SARS-CoV-2 pathogenesis and endothelial inflammatory responses using humanized K18-hACE2 mice. Survival was reduced to 20% in aged mice (85–112 weeks) versus 50% in young mice (12–15 weeks) at 10 days post infection (dpi). Bulk RNA-sequencing of endothelial cells from mock and infected mice at 2dpi of both age groups (aged: 72–85 weeks; young: 15 weeks) showed substantially lower significant differentially regulated genes in infected aged mice than in young mice (712 versus 2294 genes). Viral recognition and anti-viral pathways such as RIG-I-like receptor signaling, NOD-like receptor signaling and interferon signaling were regulated in response to SARS-CoV-2. Young mice showed several fold higher interferon responses (Ifitm3, Ifit1, Isg15, Stat1) and interferon-induced chemokines (Cxcl10 and Cxcl11) than aged mice. Endothelial cells from infected young mice displayed elevated expression of chemokines (Cxcl9, Ccl2) and leukocyte adhesion markers (Icam1) underscoring that inflammation of lung endothelium during infection could facilitate leukocyte adhesion and thromboinflammation. TREM1 and acute phase response signaling were particularly prominent in endothelial cells from infected young mice. Immunohistochemistry was unable to detect viral protein in pulmonary endothelium. In conclusion, our data demonstrate that the early host response of the endothelium to SARS-CoV-2 infection declines with aging, which could be a potential contributor to disease severity.