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The prevalence of low virulence classical swine fever virus (CSFV) strains makes viral eradication difficult in endemic countries. However, the determinants for natural CSFV attenuation and persistence in the field remain unidentified. The aim of the present study was to assess the role of the RNase activity of CSFV Erns in pathogenesis, immune response, persistent infection, and viral transmission in pigs. To this end, a functional cDNA clone pPdR-H30K-36U with an Erns lacking RNase activity was constructed based on the low virulence CSFV field isolate Pinar de Rio (PdR). Eighteen 5-day-old piglets were infected with vPdR-H30K-36U. Nine piglets were introduced as contacts. The vPdR-H30K-36U virus was attenuated in piglets compared to the parental vPdR-36U. Only RNA traces were detected in sera and body secretions and no virus was isolated from tonsils, showing that RNase inactivation may reduce CSFV persistence and transmissibility. The vPdR-H30K-36U mutant strongly activated the interferon-α (IFN-α) production in plasmacytoid dendritic cells, while in vivo, the IFN-α response was variable, from moderate to undetectable depending on the animal. This suggests a role of the CSFV Erns RNase activity in the regulation of innate immune responses. Infection with vPdR-H30K-36U resulted in higher antibody levels against the E2 and Erns glycoproteins and in enhanced neutralizing antibody responses when compared with vPdR-36U. These results pave the way toward a better understanding of viral attenuation mechanisms of CSFV in pigs. In addition, they provide novel insights relevant for the development of DIVA vaccines in combination with diagnostic assays for efficient CSF control. info:eu-repo/semantics/publishedVersion

Changes in the intestinal microbiota indirectly impact the health of mucosa distal to the intestine, particularly the respiratory tract. However, the effects of intestinal microbiota dysbiosis on the regulation of respiratory syncytial virus (RSV) infection are not clear. In this study, we examined the effects of altering the intestinal microbiota on the pulmonary immune response against RSV infection. BALB/c mice were treated with streptomycin before infection with RSV to study the altered immune response. The ingestion of streptomycin led to a marked alteration in the intestinal microbiota with a reduced abundance of Lactobacillus and Clostridium genera, followed by greatly aggravated pulmonary inflammation in response to RSV infection. This aggravated inflammation was associated with a dysregulated immune response against RSV infection, characterized by the increased expression of IFN-γ and IL-17 and increased pulmonary M1-like macrophage polarization, and decreased expression of IL-5. Supplementation of Clostridium butyricum (CB) prevented aggravated inflammation and the dysregulated immune response characterized by greater M2 polarization of pulmonary macrophages and decreased release of IFN-γ and IL-17 as well as increased IL-5 levels. Furthermore, in vitro and in vivo experiments identified that butyrate, the main metabolite produced by CB, promoted M2 polarization of macrophages in RSV-infected mice exposed to streptomycin. Together, these results demonstrate the mechanism by which intestinal microbiota modulate the pulmonary immune response to RSV infection.

Osteosarcoma (OS) is a malignant tumor commonly observed in adolescents, who experience relapse and metastasis (30% of the total cases). Its progression is attributed to immune escape mediated by immune checkpoints. However, the intercellular connection between tumor cells and T cells remain unclear. This study was conducted to explore the effects of PD-L1-loaded exosomes on the tumor growth of OS. The exosomes were extracted from cells and tissues through ultracentrifugation. IFN-γ production was determined to evaluate the activity of Jurkat cells. The in vivo growth of OS cells was examined using a C3H xenograft model in mice, tumor volumes were monitored, and the proportion of CD3 + T cells in tumor tissues was detected. Results revealed that PD-L1 was significantly upregulated in the OS cell lines. MG63 and Saos-2 cells were the most abundant in PD-L1, so they were selected as investigation targets. PD-L1 was found to be also highly expressed in the exosomes isolated from MG63 and Saos-2 cells. The exosomes elicited significant inhibitory effects on IFN-γ secretion in Jurkat cells, which were abolished by the PD-L1 antibody or siRNAs. The in vivo growth of C3H cells was significantly facilitated by the overexpression of mPD-L1 or by the administration of mPD-L1-overloaded exosomes. The infiltration of CD3 + T cells was also decreased. The exosomes extracted from clinical PD-L1-positive OS tissues showed a promising inhibitory property against activated T cells. Therefore, PD-L1-loaded exosomes extracted from OS cells aggravated OS progression by suppressing T cell activities., Graphical abstract

Tuberculosis continues to be an important public health problem. Particularly considering Beijing-family strains of Mycobacterium tuberculosis, which have been associated with drug-resistance and hypervirulence. The Beijing-like SIT190 (BL) is the most prevalent Beijing strain in Colombia. The pathogenic mechanism and immune response against this pathogen is unknown. Thus, we compared the course of pulmonary TB in BALB/c mice infected with Classical-Beijing strain 391 and BL strain 323. The disease course was different among infected animals with Classical-Beijing and BL strain. Mice infected with BL had a 100% mortality at 45 days post-infection (dpi), with high bacillary loads and massive pneumonia, whereas infected animals with Classical-Beijing survived until 60 dpi and showed extensive pneumonia and necrosis. Lung RNA extraction was carried out at early (day 3 dpi), intermediate (day 14 dpi), and late (days 28 and 60 dpi) time points of infection. Transcriptional analysis of infected mice with Classical-Beijing showed several over-expressed genes, associated with a pro-inflammatory profile, including those for coding for CCL3 and CCL4 chemokines, both biomarkers of disease severity. Conversely, mice infected with BL displayed a profile which included the over-expression of several genes associated with immune-suppression, including Nkiras, Dleu2, and Sphk2, highlighting an anti-inflammatory milieu which would allow high bacterial replication followed by an intense inflammatory response. In summary, both Beijing strains induced a non-protective immune response which induced extensive tissue damage, BL strain induced rapidly extensive pneumonia and death, whereas Classical-Beijing strain produced slower extensive pneumonia later associated with extensive necrosis. Abbreviations Mtb: Mycobacterium tuberculosis; SIT: Spoligotype International Type; TB: Tuberculosis; CTB: Classical-typical Beijing; BL: Beijing-Like; CCL3: Chemokine (C-C motif) ligand 3 (CCL3); CCL4: Chemokine (C-C motif) ligand four (CCL4); WHO: World health Organization; DR: Direct Repeats; IFN-γ: Interferon Gamma; IL: Interleukin; TGF-β: Transforming Growth Factor Beta; XDR: Extremely Drug Resistant; MDR: Multi Drug Resistant; MIRU-VNTR: Mycobacterial Interspersed Repetitive Units–Variable Number Tandem repeats; OADC: Oleic Albumin Dextrose Catalase; ATCC: American Type Culture Collection; MOI: Multiplicity of Infection; CFUs: Colony Forming Units; ELISA: enzyme-linked immunosorbent assay; qRT-PCR: Real-Time Quantitative Reverse Transcription PCR; RNA-seq: Ribonucleic Acid sequencing; RIN: RNA Integrity Number; RNA: Ribonucleic Acid; DNA: Deoxyribonucleic Acid; dsDNA HS: Double stranded Deoxyribonucleic Acid High Sensitivity; RAI: Red de Apoyo à la Investigacion, Mexico City, Mexico; DEG: Differential Expressed Genes; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; ORA: Over-Representation Analysis; SNPs: Single Nucleotide Polymorphisms; TNFα: Tumoral necrosis factor alpha; DE: Differential Expression; EPA: Enrichment Pathways Analysis; TLR: Toll-Like receptor; NLRP: NOD-like receptor with Pyrin domain; tRNA: Transfer RNA; MAPK: Mitogen-Activated Protein Kinase; NK: Natural killer; ATP: Adenosine Triphosphate; DGC: dystrophin-glycoprotein complex; PDIM: Ptiocerol Dimicocerosate; NCBI: National Center for Bioinformatics Information

Surra, one of the most important animal diseases with economic consequences in Asia and South America, is caused by Trypanosoma evansi. However, the mechanism of immune evasion by T. evansi has not been extensively studied. In the present study, T. evansi extracellular vesicles (TeEVs) were characterized and the role of TeEVs in T. evansi infection were examined. The results showed that T. evansi and TeEVs could activate TLR2-AKT pathway to inhibit the secretions of IL-12p40, IL-6, and TNF-α in mouse BMDMs. TLR2−/- mice and mice with a blocked AKT pathway were more resistant to T. evansi infection than wild type (WT) mice, with a significantly lower infection rate, longer survival time and less parasite load, as well as an increased secretion level of IL-12p40 and IFN-γ. Kinetoplastid membrane protein-11 (KMP-11) of TeEVs could activate AKT pathway and inhibit the productions of IL-12p40, TNF-α, and IL-6 in vitro. TeEVs and KMP-11 could inhibit the productions of IL-12p40 and IFN-γ, promote T. evansi proliferation and shorten the survival time of infected mice in vivo. In conclusion, T. evansi could escape host immune response through inhibiting the productions of inflammatory cytokines via secreting TeEVs to activate TLR2-AKT pathway. KMP-11 in TeEVs was involved in promoting T. evansi infection. Extracellular vesicles (EVs) secreted by Trypanosoma evansi (T. evansi) activate the TLR2-AKT signaling pathway to inhibit the production of inflammatory cytokines, thereby escaping the host’s immune response. Kinetoplastid membrane protein-11 (KMP-11) in EVs is related to the promotion of T.evansi infection via AKT pathway., Graphical abstract

Aryl hydrocarbon receptor (AHR) plays an important role in tumor development. However, its function in cervical cancer has not been fully elucidated. We evaluated the ten genes that are predicted to associate with AHR protein interaction. The comprehensive scores were: CYP1A1, ARNT2, HSP90AA1, ARNT, AIP, PTGES3, HSP90AB1, CYP1B1, ESR1, MAF, respectively. In addition, we showed that levels of AHR and its related genes were correlated with the immune infiltration and expression of immuno-regulators (immunoinhibitors, immunostimulators, MHC molecules) levels in cervical cancer. High expression of AHR, CYP1A1, HSP90AA1, and HSP90AB1 and low expression of ESR1 were negatively correlated with the prognoses of cervical cancer patients. The Cox multivariate regression showed that high expression of AHR (HR = 1.874, 95% CI = 1.069–3.285, P= 0.028) and CYP1A1 (HR = 1.822, 95%CI = 1.077–3.080, P= 0.025) were risk factors for prognosis in patients with cervical cancer. IHC results indicated that AHR and CYP1A1 were widely expressed in cervical cancer. These findings suggest that AHR and CYP1A1 may serve as prognostic biomarkers for determining prognosis and immune infiltration in cervical cancer.

Rationale: Stroke is a leading causes of human death worldwide. Ischemic damage induces the sterile neuroinflammation, which directly determines the recovery of patients. Lipids, a major component of the brain, significantly altered after stroke. Cholesterol sulfate, a naturally occurring analog of cholesterol, can directly regulate immune cell activation, indicating the possible involvement of cholesterol metabolites in neuroinflammation. Sulfotransferase family 2b member 1 (Sult2b1) is the key enzyme that catalyzes the synthesis of cholesterol sulfate. This study aimed to investigate the function of Sult2b1 and cholesterol sulfate in the neuroinflammation after ischemic stroke. Methods and Results: Sult2b1-/- and wild-type mice were subjected to transient middle cerebral artery occlusion. Our data showed that Sult2b1-/- mice had larger infarction and worse neurological scores. To determine whether immune cells were involved in the worsening stroke outcome in Sult2b1-/- mice, bone marrow transplantation, immune cell depletion, and adoptive monocyte transfer were performed. Combined with CyTOF and immunofluorescence techniques, we demonstrated that after stroke, the peripheral monocyte-derived macrophages were the dominant cell type promoting the pro-inflammatory status in Sult2b1-/-mice. Using primary bone marrow-derived macrophages, we showed that cholesterol sulfate could attenuate the pro-inflammatory polarization of macrophages under both normal and oxygen-glucose deprivation conditions by regulating the levels of nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species (ROS), and activating the AMP-activated protein kinase (AMPK) - cAMP responsive element-binding protein (CREB) signaling pathway. Conclusions: Sult2b1-/- promoted the polarization of macrophages into pro-inflammatory status. This trend could be attenuated by adding cholesterol sulfate, which promotes the polarization of macrophages into anti-inflammatory status by metabolic regulation. In this study, we established an inflammation-metabolism axis during the macrophage polarization after ischemic stroke.

Neutrophils are prominent immune components of solid tumors, which can protect against the onset of cancer (N1) or have pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN, a rare subset in non-pathological conditions, have been extensively studied in cancer, due to their frequency in this disease and their pro-tumor phenotype. However, this has been mainly demonstrated in animal models and proper validation in humans is an urgent need. Here, we further enlighten the clinical impact of LDN in a cohort of breast cancer (BC) patients. We observed that LDN were practically absent in healthy donors’ blood, while were significantly increased in the blood of BC patients, particularly with metastatic disease. Relevant for a clinical translation, within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than in responders. The association of a higher incidence of circulating LDN and the worse prognosis of BC patients could be explained by the pro-tumor/immunosuppressive characteristics exhibited by these cells. Namely, there are more LDN expressing the immunosuppressive marker PD-L1, than HDN. Additionally, LDN also showed increased expression of activation markers; a robust formation of neutrophil extracellular traps; an augmented phagocytic activity; and a higher capacity to release reactive oxygen species, which may contribute for tumor development and metastization. Moreover, the percentage of LDN in BC patients’ blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with the immunosuppressive CCR4+ regulatory T cells, corroborating their impairment on the anti-tumor immune responses, which was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a clinical meaningful biomarker of BC response to treatment and opens new avenues for developing targeted immunotherapies.

Hepatocellular carcinoma (HCC) is the most common high malignancy with insidious onset, invasive fast-growing, high recurrence rate and fatality. YTH domain family plays essential roles in development of HCC. However, the biological function of YTH domain family in HCC have not been clarified. Here, through evaluating the expression profiles of YTH domain family, we found that upregulated YTHDF1 might be more significant and valuable in development and progression of HCC. There was a strong correlation between YTHDC1, YTHDF1 and YTHDF2 and pathological stage of HCC patients. Kaplan-Meier plotter revealed that HCC patients with high level of YTHDF1 and YTHDF2 were highly related to a shorter overall survival time, and low level of YTHDF1 (p = 0.0017) has an important association with a longer progression-free survival time. Genetic alterations using cBioPortal revealed that the alteration rates of YTHDF3 were the highest. We also found that the functions of YTH domain family were linked to several cancer-associated pathways, including peptidyl-serine modification, peptidyl-tyrosine modification and negative regulation of cellular component movement. TIMER database indicated that the YTH domain family had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Ualcan databases revealed that the global methylation levels of YTHDC1 was higher in HCC patients, while YTHDF2 was lower in HCC patients. In conclusion, our findings will enhance the understanding of YTH domain family in HCC pathology, and provide novel insights into YTH-targeted therapy for HCC patients.

This study addresses the potential to reverse age-associated morbidity by establishing methods to restore the aged hematopoietic system. Parabiotic animal models indicated that young secretome could restore aged tissues, leading us to establish a heterochronic transwell system with aged mobilized peripheral blood (MPB), co-cultured with young MPB or umbilical cord blood (UCB) cells. Functional studies and omics approaches indicate that the miRNA cargo of microvesicles (MVs) restores the aged hematopoietic system. The in vitro findings were validated in immune deficient (NSG) mice carrying an aged hematopoietic system, improving aged hallmarks such as increased lymphoid:myeloid ratio, decreased inflammation and cellular senescence. Elevated MYC and E2F pathways, and decreased p53 were key to hematopoietic restoration. These processes require four restorative miRs that target the genes for transcription/differentiation, namely PAX and phosphatase PPMIF. These miRs when introduced in aged cells were sufficient to restore the aged hematopoietic system in NSG mice. The aged MPBs were the drivers of their own restoration, as evidenced by the changes from distinct baseline miR profiles in MPBs and UCB to comparable expressions after exposure to aged MPBs. Restorative natural killer cells eliminated dormant breast cancer cells in vivo, indicating the broad relevance of this cellular paradigm - preventing and reversing age-associated disorders such as clearance of early malignancies and enhanced responses to vaccine and infection.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors worldwide. The clinical treatment of ccRCC is strongly associated with the tumor microenvironment (TME). Identifying potential markers of ccRCC is important to improve prognosis. Therefore, in the present study, the levels of immune/stromal components and the proportion of tumor-infiltrating immune cells (TIICs) were determined in 611 ccRCC samples using the ESTIMATE and CIBERSORT analytical tools. Subsequently, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified by univariate Cox regression analysis, protein-protein interaction (PPI) networks and clinical survival analysis to be associated with ccRCC prognosis. At the same time, the abundance of HSD11B1 increased significantly in ccRCC was verified by western blotting, RT‑qPCR and immunostaining analysis. Furthermore, Gene Set Enrichment Analysis (GSEA) and TME suggested that HSD11B1 was involved in TME immune-related status. Taken together, the results of the present study demonstrated that HSD11B1 is a potential prognostic biomarker associated with immune cell infiltration in ccRCC.

Spindle and kinetochore associated (SKA) complex subunit, which maintains the stability of mitotic metaphase, with emerging research implying its effect as a carcinogenic regulator in cancer. However, its potential role in BC has not been fully elucidated. ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER databases were performed to analyze the expression, prognosis, mutation, immune infiltration and potential biological mechanisms of SKA1/2/3 in BC. Our results showed that SKA1/2/3 expression was upregulated in BC. Survival analysis reveals that SKA3 overexpression was associated with poor overall survival (OS), relapse-free survival (RFS), post-progression survival (PPS) and distant metastasis-free survival (DMFS). SKA1 overexpression was associated with poor OS, RFS and DMFS while SKA2 overexpression was only associated with RFS and DMFS. Notably, the results implied that SKA1 has a good prognostic value in HER2-positive BC. Besides, the genetic alterations of SKA were investigated and the altered group correlated with shorter progress-free survival (PFS) and disease-specific survival (DSS). GO and KEGG analysis showed that SKA1/2/3 were implicated in regulating cell cycle, p53 signaling pathway and DNA replication. The 10 Hub genes in the protein network were upregulated in BC and related to poorer prognosis. Additionally, SKA1/2/3 expression was negatively correlated with infiltration of various immune cells with antitumor effects, whereas positively correlated with the expression of immune checkpoints molecules. Further experiments revealed that SKA1/2/3 silencing markedly impeded the proliferation and migration of BC cells. Herein, our study firmly shows that SKA genes may serve as a promising therapeutic target for patients with BC.

Cervical cancer (CC) is one of the most common malignancies encountered in gynecology practice. However, there is a paucity of information about specific biomarkers that assist in the diagnosis and prognosis of CC. Pyroptosis is a form of programmed cell death whose different elements are related to the occurrence, invasion, and metastasis of tumors. However, the role of pyroptosis phenomena in the progression of CC has not yet been elucidated. This study focuses on the development of a pyroptosis-associated prognostic signature for CC using integrated bioinformatics to delineate the relationships among the signature, tumor microenvironment, and immune response of the patients. In this respect, we identified a prognostic signature that depends on eight pyroptosis-related genes (PRGs) that designate with better prognostic survival in the low-risk group (P

Pannexin 1 (PANX1) channel is a critical ATP-releasing pathway that modulates tumor immunity, progression, and prognosis. However, the roles of PANX1 in different cancers remain unclear. We analyzed the expression of PANX1 in human pan-cancer in the Oncomine and GEPIA2.0 databases. The prognostic value of PANX1 expression was determined using Kaplan-Meier plotter and OncoLnc tools. The correlation between PANX1 and tumor-infiltrating immune cells was investigated using the TIMER 2.0. In addition, the relationship between PANX1 and immunomodulators was explored using TISIDB. Finally, gene set enrichment analysis (GSEA) was performed utilizing LinkedOmics. The results indicated that PANX1 was overexpressed in most cancers compared to normal tissues. The high expression of PANX1 was associated with poor prognosis in multiple tumors, especially in pancreatic adenocarcinoma (PAAD). In addition, PANX1 was correlated with a variety of immunomodulators, such as CD274, IL10, CD276, IL2RA, TAP1, and TAP2. PANX1 expression level was significantly related to infiltration of multiple immune cells in many cancers, including cancer associated fibroblast, macrophage, and neutrophil cells. Further analysis revealed that PANX1 was significantly associated with T cells CD8+ (rho = 0.524, P = 1.94e-13) and Myeloid dendritic cell (rho = 0.564, P = 9.45e-16). GSEA results showed that PANX1 was closely associated with leukocyte cell-cell adhesion, endoplasmic reticulum lumen, ECM-receptor interaction, and Focal adhesion pathways in PAAD. PANX1 expression was higher in pan-cancer samples than in normal tissues. The high expression of PANX1 was associated with poor outcome and immune infiltration in multiple cancers, especially in PAAD.

Accumulating evidence suggests that two chronic respiratory diseases, nontuberculous mycobacterium (NTM)-pulmonary disease (PD) and allergic asthma, are frequently present together and that they likely influence the disease development and progression of each other. However, their precise interactions regarding the pathogenesis of comorbid diseases versus that of individual diseases are not well understood. In this study, comorbid diseases (i.e., Mycobacteria avium (Mav) pulmonary infection (PI) (Mav-PI) and ovalbumin-induced allergic asthma) were established in mice in different orders and at different time periods. Individual disease-specific characteristics, including alterations in immune cell populations and antigen-specific immune responses, were analyzed and compared. To assess Mav-PI pathogenesis, lung inflammation and bacterial burden levels were also determined. Allergic asthma induction in the presence of Mav-PI markedly aggravated Mav-PI pathogenesis by increasing the bacterial burden and the severity of lung inflammation. Interestingly, the general outcome of allergic asthma with goblet cell hyperplasia was alleviated at a chronic stage in the comorbid mouse model. Overall, the increase in the number of Mav CFUs was inversely correlated with the Mav-specific Th17 response, as confirmed by comparing BALB/c and C57BL/6J mice. Overall, the pathogenesis of existing Mav-PI is more severely affected by allergen exposure than vice versa. This Mav-PI exacerbation is associated with disruption of Mav-specific Th17 responses. This study provides the first evidence that the Mav-specific Th17 response plays an important role in the control of Mav pathogenesis in the presence of allergic asthma, indicating that targeting the Th17 response has therapeutic potential for NTM-PD accompanied by allergic asthma.

Cytotoxic T cells expressing cell surface CD8 played a key role in anti-cancer immunotherapy, including kidney renal clear cell carcinoma (KIRC). Here we set out to comprehensively analyze and evaluate the significance of CD8+ T cell-related markers for patients with KIRC. We checked immune cell response in KIRC and identified cell type-specific markers and related pathways in the tumor-infiltrating CD8+ T (TIL-CD8T) cells. We used these markers to explore their prognostic signatures in TIL-CD8+ T by evaluating their prognostic efficacy and group differences at various levels. Through pan-cancer analysis, 12 of 63 up-regulated and 162 of 396 down-regulated genes in CD8+ T cells were found to be significantly correlated with the survival prognosis. Based on our highly integrated multi-platform analyses across multiple datasets, we constructed a 6-gene risk scoring model specific to TIL-CD8T. In this model, high TIL-CD8 sig score was corresponding to a higher incidence frequency of copy number variation and drug sensitivity to sorafenib. Moreover, the prognosis of patients with the same or similar immune checkpoint gene levels could be distinguished from each other by TIL-CD8 sig score.

Breast cancer (BC) is the most common malignancy with high morbidity and mortality in females worldwide. Emerging evidence indicates that transferrin receptor 1 (TfR1) plays vital roles in regulating cellular iron import. However, the distinct role of TfR1 in BC remains elusive. TfR1 expression was investigated using the TCGA, GEO, TIMER, UALCAN and Oncomine databases. The prognostic potential of TfR1 was evaluated by Kaplan-Meier (KM) plotter and univariate and multivariate Cox regression analyses. Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to explore the molecular mechanism of TfR1. The potential link between TfR1 expression and infiltrating abundances of immune cells was examined through the TIMER and CIBERSORT algorithm. The expression of TfR1 was dramatically upregulated in BC tissues. Increased TfR1 expression and decreased methylation levels of TfR1 were strongly correlated with multiple clinicopathological parameters. Elevated TfR1 expression was associated with a poor survival rate in BC patients. The nomogram model further confirmed that TfR1 could act as an independent prognostic biomarker in BC. The results of GO, KEGG and GSEA revealed that TfR1 was closely correlated with multiple signaling pathways and immune responses. Additionally, TfR1 was positively associated with the infiltration abundances of six major immune cells, including CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and dendritic cells in BC. Interestingly, TfR1 influenced prognosis partially through immune infiltration. These comprehensive bioinformatics analyses suggest that TfR1 is a new independent prognostic biomarker and a potential target for immunotherapy in BC.

Introduction: Squamous cell carcinoma (SCC) is the most common skin cancer with a high rate of death. Different lymphocyte populations play an important role in modulating the immune response in the tumor microenvironment. The increase in the proportion of cluster of differentiation (CD)4+ CD25+ regulatory T-cell (Treg) lymphocytes is associated, in different studies, with the increase of the cell multiplication rate. Aim: To analyze the Treg lymphocyte subpopulations and to correlate the results with the presence of the CD8+ cytotoxic T-cell (Tc) lymphocyte population. Materials and Methods: Sixty primary skin SCC specimens were incubated with anti-CD8 (clone SP57) rabbit monoclonal antibody and anti-CD25 (clone 4C9) mouse monoclonal antibody. Results: The ratio of the intratumoral/peritumoral CD4+ CD25+ forkhead box protein p3 (Foxp3) lymphocytes was 0.46, emphasizing that at tumor margins, where tumor aggressiveness is higher, these lymphocytes subpopulations facilitate tumor progression. The comparative analysis of the tumor microenvironment profile revealed that in the case of intratumoral immune response, the number of Tc-type lymphocytes (CD8+) was 3.34 times higher compared to Treg lymphocytes (p

Despite the well-established association of gene expression deregulation with low muscle mass (LMM), the associated biological mechanisms remain unclear. Transcriptomic studies are capable to identify key mediators in complex diseases. We aimed to identify relevant mediators and biological mechanisms associated with age-related LMM. LMM-associated genes were detected by logistic regression using microarray data of 20 elderly women with LMM and 20 age and race-matched controls extracted from our SPAH Study (GSE152073). We performed weighted gene co-expression analysis (WGCNA) that correlated the identified gene modules with laboratorial characteristics. Gene enrichment analysis was performed and an LMM predictive model was constructed using Support Vector Machine (SVM). Overall, 821 discriminating transcripts clusters were identified (|beta coefficient| >1; p-value

The present study was aimed to evaluate the expression profile of Zinc finger C3H1 domain-containing protein (ZFC3H1) using bioinformatic analysis of public datasets from The Cancer Genome Atlas database (TCGA). The results showed that the expression levels of ZFC3H1 were notably lower than the corresponding non-cancerous tissues in prostate adenocarcinoma (PRAD), and patients in the high ZFC3H1-expression group showed poor survival. We hypothesized that the low expression of ZFC3H1 in tumor tissue might have be an inhibitory effect on the autoimmune system. We predicted the regulatory target and protein interaction partner network of ZFC3H1, and identified a PPI network composed of 26 node genes in PRAD. Furthermore, we found that the expression levels of MPHOSPH6 (encoding M-phase phosphoprotein 6) and MRPS31 (encoding mitochondrial ribosomal protein S31) were lower in PRAD tissues than in non-cancerous tissues, and the survival time of patients with high MPHOSPH6 and MRPS31 expression was poor. To further demonstrate the role of ZC3H1 in PRAD, we knocked-down the ZFC3H1 expression and found that the inhibition of ZFC3H1 significantly inhibited PRAD cell migration and invasion. Furthermore, ZFC3H1 siRNA treatment could reduce cell viability and increase the number of apoptotic cells in PRAD cells. Taken together, ZFC3H1 could represent a new marker for PRAD prognosis and provide a reference for the development of new therapies to treat PRAD.

Microglia are the primary cellular source of type I interferons (I-IFNs) in the brain upon neurotropic virus infection. Although the I-IFN-based antiviral innate immune response is crucial for eliminating viruses, overproduction led to immune disorders. Therefore, the relatively long-lasting I-IFNs must be precisely controlled, but the regulatory mechanism for the innate antiviral response in microglia remains largely unknown. Long non-coding RNAs (lncRNAs) are being recognized as crucial factors in numerous diseases, but their regulatory roles in the innate antiviral response in microglia are undefined. Methods: The high-throughput RNA sequencing was performed to obtain differentially expressed lncRNAs (DELs) in primary microglia infected with or without the neurotropic herpes simplex virus type 1 (HSV-1). We selected four DELs ranked in the top 15 in basic level and their fold change induced by HSV-1, i.e., FPKMHSV-1/FPKMCells.We subsequently found a key lncRNA affecting the innate antiviral response of microglia significantly. We next used dual-luciferase reporter assays, bioinformatical tools, and truncation mutants of both lncRNA and targeted proteins to elucidate the downstream and upstream mechanism of action of lncRNA. Further, we established microglia-specific knock-in (KI) mice to investigate the role of lncRNA in vivo. Results: We identified a long intergenic non-coding RNA, linc-AhRA, involved in regulating the innate antiviral response in murine microglia. linc-AhRA is activated by aryl hydrocarbon receptor (AhR) and restricts I-IFN production in microglia upon neurotropic herpesvirus infection and innate immune stimulation. Mechanistically, linc-AhRA binds to both tripartite motif-containing 27 (TRIM27) and TANK-binding kinase 1 (TBK1) through its conserved 117nt fragment as a molecular scaffold to enhance TRIM27-TBK1 interaction. This interaction facilitates the TRIM27-mediated ubiquitination of TBK1 and results in ubiquitin-proteasome-dependent degradation of TBK1. Consequently, linc-AhRA suppresses I-IFN production through facilitating TBK1 degradation and limits the microglial innate immune response against neurotropic herpesvirus infection. Microglia-specific KI of linc-AhRA mice shows a weakened antiviral immune response upon neurotropic herpesvirus challenge due to a reduction of TBK1 in microglia. Conclusion: Our findings indicate that linc-AhRA is a negative regulator of I-IFN production in microglia to avoid excessive autoimmune responses. These findings uncover a previously unappreciated role for lncRNA conserved fragments in the innate antiviral response, providing a strong foundation for developing nucleotide drugs based on conserved functional fragments within lncRNAs., Theranostics, 11(19), pp. 9623-9651; 2021

Previous studies have shown that long‐term light or moderate fasting such as intermittent fasting can improve health and prolong lifespan. However, in humans short‐term intensive fasting, a complete water‐only fasting has little been studied. Here, we used multi‐omics tools to evaluate the impact of short‐term intensive fasting on immune function by comparison of the CD45+ leukocytes from the fasting subjects before and after 72‐h fasting. Transcriptomic and proteomic profiling of CD45+ leukocytes revealed extensive expression changes, marked by higher gene upregulation than downregulation after fasting. Functional enrichment of differentially expressed genes and proteins exposed several pathways critical to metabolic and immune cell functions. Specifically, short‐term intensive fasting enhanced autophagy levels through upregulation of key members involved in the upstream signals and within the autophagy machinery, whereas apoptosis was reduced by down‐turning of apoptotic gene expression, thereby increasing the leukocyte viability. When focusing on specific leukocyte populations, peripheral neutrophils are noticeably increased by short‐term intensive fasting. Finally, proteomic analysis of leukocytes showed that short‐term intensive fasting not only increased neutrophil degranulation, but also increased cytokine secretion. Our results suggest that short‐term intensive fasting boost immune function, in particular innate immune function, at least in part by remodeling leukocytes expression profile., Short‐term intensive fasting remodels innate immunity in humans through improving neutrophil function with elevated secretion of cytokines, together with upregulation of autophagy and downregulation of apoptosis.

Ventricular remodeling following myocardial infarction (MI) is a major cause of heart failure, a condition prevalent in older individuals. Following MI, immune cells are mobilized to the myocardium from peripheral lymphoid organs and play an active role in orchestrating repair. While the effect of aging on mouse bone marrow (BM) has been studied, less is known about how aging affects human BM cells and their ability to regulate repair processes. In this study, we investigate the effect aging has on human BM cell responses post‐MI using a humanized chimeric mouse model. BM samples were collected from middle aged (mean age 56.4 ± 0.97) and old (mean age 72.7 ± 0.59) patients undergoing cardiac surgery, CD34+/− cells were isolated, and NOD‐scid‐IL2rγnull (NSG) mice were reconstituted. Three months following reconstitution, the animals were examined at baseline or subjected to coronary artery ligation (MI). Younger patient cells exhibited greater repopulation capacity in the BM, blood, and spleen as well as greater lymphoid cell production. Following MI, CD34+ cell age impacted donor and host cellular responses. Mice reconstituted with younger CD34+ cells exhibited greater human CD45+ recruitment to the heart compared to mice reconstituted with old cells. Increased cellular responses were primarily driven by T‐cell recruitment, and these changes corresponded with greater human IFNy levels and reduced mouse IL‐1β in the heart. Age‐dependent changes in BM function led to significantly lower survival, increased infarct expansion, impaired host cell responses, and reduced function by 4w post‐MI. In contrast, younger CD34+ cells helped to limit remodeling and preserve function post‐MI., To study the effect aging has on human cell responses post‐MI, we utilized a xenograft mouse (NSG) model using BM from middle aged (Y‐CD34+) and old patients (O‐CD34+). Our results demonstrate that O‐CD34+ reconstituted mice exhibit impaired donor and host cell responses while Y‐CD34+ reconstituted mice exhibit a greater donor lymphocyte and host myeloid cell responses post‐MI. Differences in cellular responses are associated with improved cardiac function in Y‐CD34+ reconstituted mice post‐MI.

Background The characteristic features of the immune responses of COVID‐19 patients and how they reflect lung involvement have not been clearly elucidated. Aim The aim of this study was to examine the immune status and the correlations thereof with chest CT scores and lung involvement of patients with COVID‐19. Methods In this retrospective and single‐center study, 72 patients with laboratory‐confirmed COVID‐19 were recruited. The counts of peripheral lymphocyte subsets (CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells and CD16+ 56+ NK cells) and those of serum immunoglobulins (IgA, IgG, IgM) were measured and their associations with chest CT scores analysed. Results The proportions of lymphopenia in patients with extensive lung involvement were twice that in the general study population. In the severe disease group, the levels of total lymphocytes, T cells, B cells, NK cells; and serum IgA levels, were significantly lower than in the mild disease group (all P