Infection by exosome-carried Coxsackievirus B3 induces immune escape resulting in an aggravated pathogenesis.

Increasing evidence has shown that extracellular vesicles or exosomes released from virus-infected cells contain viral particles, genomes, or other pathogenic factors that move to neighbor cells, contributing to virus dissemination and productive infection. Our recent study demonstrated that exosomes carrying CVB3 virions exhibited greater infection efficiency than free virions because they accessed various entry routes, overcoming restrictions to viral tropism. However, the pathogenicity of exosomes carried CVB3 and their effect on immunological properties have not yet been completely explained. In the current study, we sought to explore whether exosomes exert their effect on the CVB3-induced pathogenesis or evade the immune attack. Our results showed that exosomes-carried CVB3 could effectively infect viral receptor-negative immune cells in vivo, resulting in inducing immune system loss. Importantly, the exosomes-carried CVB3 had the ability to escape the neutralizing antibodies activity resulting in inducing the severe onset of myocarditis. Using the genetically engineered mouse with deficiency of exosomes, we observed that the exosomes-carried CVB3 reinforced an aggravated pathogenesis. By understanding how exosomes promote the course of viral disease, clinical applications of exosomes can be developed.

Enterovirus 71-induced autophagosome fusion with multivesicular bodies facilitates viral RNA packaging into exosomes.

Exosomes have been shown to release from cells infected by viruses and deliver viral particles, genomes, and other viral genetic elements to neighboring cells resulting in modulating host immune response. Our previous study demonstrated that exosomes released from Enterovirus 71 (EV71)-infected cells contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182, which can be successfully transferred to recipient/target cells to establish productive infection. However, the molecular mechanisms that control viral genome package into exosomes are still unclear. In this study, we showed that the EV71-induced autophagy response contributed to viral genome package into exosomes rather than process of exosomes biogenesis. Further study showed that the autophagosomes accumulation facilitated their fusion with MVBs, which resulted in EV71 RNA package into exosome vesicles. Moreover, prevention of autophagosomes-MVBs fusion could abolish this sorting of viral RNA into exosomes. Knockdown of GW182 or Ago2 could weaken the replication ability of exosomal EV71 RNA in recipient cells through decreasing the amount of miR-146a in exosomes, but did not affect the package of viral RNA into exosomes. Our findings strongly suggested that the accumulation of autophagosomes that were induced by EV71 infection play a key role on viral spreading through exosome vesicles.

Identification of Immune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis.

Background: Ulcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and its incidence is steadily increasing worldwide. Intestinal immune dysfunction has been identified as a central event in UC pathogenesis. However, the underlying mechanisms that regulate dysfunctional immune cells and inflammatory phenotype remain to be fully elucidated. Methods: Transcriptome profiling of intestinal mucosa biopsies were downloaded from the GEO database. Robust Rank Aggregation (RRA) analysis was performed to identify statistically changed genes and differentially expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. CIBERSORT was used to evaluate the proportion of 22 immune cells in biopsies. Weighted co-expression network analysis (WGCNA) was used to determine key module-related clinical traits. Protein-Protein Interaction (PPI) network and Cytoscape were performed to explore protein interaction network and screen hub genes. We used a validation cohort and colitis mouse model to validate hub genes. Several online websites were used to predict competing endogenous RNA (ceRNA) network. Results: RRA integrated analysis revealed 1838 statistically changed genes from four training cohorts (adj. p-value < 0.05). GSEA showed that statistically changed genes were enriched in the innate immune system. CIBERSORT analysis uncovered an increase in activated dendritic cells (DCs) and M1 macrophages. The red module of WGCNA was considered the most critical module related to active UC. Based on the results of the PPI network and Cytoscape analyses, we identified six critical genes and transcription factor NF-κB. RT-PCR revealed that andrographolide (AGP) significantly inhibited the expression of hub genes. Finally, we identified XIST and three miRNAs (miR-9-5p, miR-129-5p, and miR-340-5p) as therapeutic targets. Conclusions: Our integrated analysis identified four hub genes (CXCL1, IL1B, MMP1, and MMP10) regulated by NF-κB. We further revealed that AGP decreased the expression of hub genes by inhibiting NF-κB activation. Lastly, we predicted the involvement of ceRNA network in the regulation of NF-κB expression. Collectively, our results provide valuable information in understanding the molecular mechanisms of active UC. Furthermore, we predict the use of AGP and small RNA combination for the treatment of UC.

Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis.

In the last few years, cellular metabolic reprogramming has been acknowledged as a hallmark of human cancer and evaluated for its crucial role in supporting the proliferation and survival of human cancer cells. In a variety of human tumours, including hepatocellular carcinoma (HCC), breast cancer and non-small-cell lung cancer (NSCLC), a large amount of carbon is reused in serine/glycine biosynthesis, accompanied by higher expression of the key glycine synthetic enzyme mitochondrial serine hydroxymethyltransferase 2 (SHMT2). This enzyme can convert serine into glycine and a tetrahydrofolate-bound one-carbon unit, ultimately supporting thymidine synthesis and purine synthesis and promoting tumour growth. In tumour samples, elevated expression of SHMT2 was found to be associated with poor prognosis. In this review, the pivotal roles of SHMT2 in human carcinogenesis are described, highlighting the underlying regulatory mechanisms through promotion of tumour progression. In conclusion, SHMT2 may serve as a prognostic marker and a target for anticancer therapies.