STAT1-dependent tolerance of intestinal viral infection

Abstract

1Recent evidence indicates that viral components of the microbiota can contribute to intestinal 2 homeostasis and protection from local inflammatory or infectious insults. However, host-derived 3 mechanisms that maintain tolerance to the virome remain largely unknown. Here, we use 4 colonization with the model commensal murine norovirus (MNV CR6) to interrogate host-5 directed mechanisms of viral tolerance, and show that STAT1 is a central coordinator of 6 tolerance following CR6 colonization. STAT1 restricts CR6 replication to the intestinal tract, 7 prevents systemic viral-induced tissue damage and disease, and regulates antiviral CD4 + and 8 CD8 + T cell responses. In contrast to systemic viral pathogens that drive T cell mediated 9 immunopathology in STAT1-deficient mice, our data indicates that loss of CD4 + or CD8 + T cells 10 and their associated effector functions has no effect on CR6-induced disease. However, 11 therapeutic administration of an antiviral compound to limit viral replication prevented viral-12 induced tissue damage and death despite ongoing dysregulated antiviral T cell responses. 13Collectively, our data uncouple the requirement for STAT1-mediated regulation of antiviral T cell 14 responses from innate immune-mediated restriction of viral replication that is necessary for 15 intestinal viral tolerance. 16 17 34 antiviral treatment can enhance DSS-induced colonic inflammation in mice 8 , indicating that even 35 in the presence of a complex microbiota, the virome (composed of bacteriophage, endogenous 36 retroviruses, and eukaryotic viruses) contributes to intestinal homeostasis. Supporting the 37 hypothesis that host-encoded mechanisms regulate and tolerate viral colonization, latent or 38 chronic viral infection can be reactivated by helminth infection in a STAT6 and interferon (IFN)g-39 dependent manner 9 . 40 41 3 MNV CR6 (CR6) demonstrates features of a mutualistic host-microbe interaction and is an 42 attractive model to interrogate commensal tolerance to a eukaryotic virus. In addition to 43 providing supportive signals in immunosufficient GF mice 7,10 , this strain can establish persistent 44 colonic infection with continued shedding for at least two months in the absence of any 45 detectable clinical or histopathological signs in wildtype (WT) mice 11 . Once MNV was 46 identified 12 , sentinel screening of animal units across North America and Europe identified its 47 57 an IL-22/STAT1-dependent mechanism limits intestinal epithelial cell (IEC)-intrinsic viral 58 replication and RV-induced intestinal pathology 22 . Following vaccinia virus infection, STAT1 59 supports optimal antiviral CD8 + T cell expansion and survival 23,24 . In contrast, STAT1-deficient 60 mice exhibit increased numbers of both CD4 + and CD8 + T cells in response to infection with 61 LCMV Armstrong, although these cells do not constrain viral replication 25 . Instead, Stat1 -/mice 62 succumb rapidly to CD4 + T cell mediated immunopathology 25 . Indeed, tissue damage caused by 63 dysregulated lymphocyte su...

Probiotics as a biotherapeutics for the management and prevention of respiratory tract diseases

“…Several other studies have demonstrated the impaired immune responses and augmented outcomes followed by bacterial and viral respiratory infections in the absence of gut microbiota 84,104,117 . Gut microbiota–derived signals have been shown to activate signal transducer and activator of transcription‐1 (STAT1), which is critically involved in antiviral gene expression 84,118 . Further, probiotic microorganisms such as Lactobacillus and Bifidobacterium have significantly reduced the occurrence of respiratory infections followed by antibiotic‐induced changes in gut microbiota composition.…”

“…84,104,117 Gut microbiota-derived signals have been shown to activate signal transducer and activator of transcription-1 (STAT1), which is critically involved in antiviral gene expression. 84,118 Further, probiotic microorganisms such as Lactobacillus and Bifidobacterium have significantly reduced the occurrence of respiratory infections followed by antibiotic-induced changes in gut microbiota composition. Probiotics can induce Treg cells, which are involved in the downregulation of allergic responses.…”

The differences in SARS-CoV and SARS-CoV-2 specific co-expression network mediated biological process in human gut enterocytes

“…The most relevant pathways encoded by them were transmembrane transport and IL4 and IL13 signaling (Supplementary Table S6). For SARS-CoV-2,the top 20 proteins were ANKRD49, GGA1, NAGLU, SORL1, TRIM59, GAS2L3, PTPRH, DRD1, RHOV, VPS35L, ZNF581, SAMD9, TBC1D3, DUOXA1, IL18, LPAR2, OPN5, GSTM3 and SPATA12 responsible for interleukin signaling pathway of the immune system (Supplementary Table S7; Supplementary Table S8) and interestingly most of them reported to be involved induced during different kind of viral infection having some role on host defense response and inflammation ( Menner et al, 2015 ; Filyk et al, 2020 ).…”

“…The proposed network-based dietary supplements/anti-inflammatory compounds discovery depends on the hypothesis that the important hub proteins that functionally govern viral infection localized in the corresponding subnetwork would be the target for compounds or dietary supplements ( Filyk et al, 2020 ). Using Comparative Toxicogenomics Database (CTD), we identified the possible dietary supplements/ant-inflammatory compounds which known to have possible interaction with the hub proteins.…”

Probiotics in Treatment of Viral Respiratory Infections and Neuroinflammatory Disorders

“…Gut bacteria regulate the activation of the interferons (IFNs) signaling, which is crucial for response against the majority of viruses, and inflammasome activity, an innate signaling pathway that is involved in defense against a subset of viruses [42]. In the steady-state, gut microbial-derived signals regulate low-level signal transducer and activator of transcription-1 (STAT1) activation [42], which is critical for IFNs signaling, and is involved in antiviral defense genes induction prior to infection and immune-mediated resistance to viral infection [42,43]. Figure 1 illustrates the role of gut microbiota in the prevention of viral respiratory infections.…”