Biology subjects

Sharon, A. J.

Publications and source records attributed to Sharon, A. J..

4 recordsLinked to original sources

bioRxiv2026

STAT1 expression in myeloid cells restrains murine norovirus-induced hepatitis and fibrosis

Background & AimsRare cases of non-hepatotropic virus (NHV) infection in humans can cause severe hepatitis and even acute liver failure. Clinically relevant animal models of NHV-induced hepatitis are limited, contributing to the incomplete understanding of pathological mechanisms. Murine norovirus (MNV) elicits hepatosplenomegaly in mice lacking the antiviral immune effector Signal Transducer and Activator of Transcription-1 (STAT1), providing a model to investigate mechanisms of NHV-induced hepatic pathology. MethodsSTAT1-sufficient and -deficient (Stat1Het, Stat1KO) littermates infected intravenously (i.v.) with MNV strain CR6 were assessed for hepatic inflammation and viral burden. Cell types and molecular pathways associated with hepatic pathology in CR6-infected Stat1KO mice were identified by flow cytometry and RNAseq of liver tissue. The relative importance of hematopoietic vs non-hematopoietic expression of STAT1 in restricting CR6 replication and maintaining tissue homeostasis was assessed in bone marrow chimeras. ResultsMNV CR6 Stat1KO mice developed severe hepatitis with patchy hepatocellular necrosis and localized enrichment of CR6-infected myeloid cells, particularly macrophages. Gene set enrichment analysis (GSEA) of hepatic biopsies isolated from CR6-infected Stat1KO mice suggested dysregulated myeloid cell activation and indicated similarities between murine and human hepatic pathologies. STAT1 expression in hematopoietic cells was protective against hepatic viral dissemination, but hematopoietic STAT1-deficiency permitted persistent hepatic MNV infection, facilitating dysregulated myeloid cell activation and hepatic fibrosis. ConclusionsThese results demonstrate that the role of STAT1 extends beyond restricting MNV dissemination and suggest that STAT1-dependent regulation of myeloid cell activation prevents acute hepatic necroinflammation and secondary fibrosis. This model of MNV-induced hepatitis may prove valuable in elucidating mechanisms of rare clinical complications. SynopsisMechanisms driving acute hepatitis caused by non-hepatotropic viruses are not well understood. We describe a model of non-hepatotropic murine norovirus infection that reliably induces liver pathology and identify a requirement for STAT1 expression in myeloid cells to promote antiviral immunity and hepatic tissue protection. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/720966v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@4ef59forg.highwire.dtl.DTLVardef@1dfac58org.highwire.dtl.DTLVardef@1abe41dorg.highwire.dtl.DTLVardef@d59e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Helminth infection induces neuroimmune remodeling and clinical remission in a mouse model of multiple sclerosis

The central nervous system (CNS) is under constant immunosurveillance and influenced by immune-related effector molecules, including type 2-associated cytokines. Long-lasting type 2 immunity elicited by intestinal helminth infections can modify immune responses and wound repair locally and in peripheral tissues, but direct effects of helminth infection on the CNS are poorly understood. Here, we explore whether naturally-evoked type 2 immune responses can modify neuroimmune interactions for therapeutic gain in a mouse model of multiple sclerosis. Chronic infection with the helminth Trichinella spiralis (Ts) remodelled the neuroimmune landscape, including establishment of a robust population of CNS-resident T helper 2 cells, which subsequently minimized CNS inflammation and demyelination during experimental autoimmune encephalomyelitis (EAE). Clinical remission could be achieved with prophylactic or therapeutic infection, was Stat6-dependent, and adoptive transfer of Th2 cells promoted remission in the absence of overt infection. These findings highlight the potential for harnessing type 2 immunity to modify outcomes of neuroinflammation and neurodegeneration. SummaryFettig et al. demonstrate that infection with the helminth Trichinella spiralis elicits rapid recruitment and sustained presence of Th2 cells in the central nervous system where they modify microglia function and are implicated in resolving autoimmune-mediated paralysis and neuroinflammation.

immunology↗

bioRxiv2022

The dietary fiber guar gum ameliorates experimental autoimmune encephalomyelitis via attenuated Th1 activation and differentiation

Dietary fibers are potent modulators of immune responses that can restrain inflammation in multiple disease contexts. However, dietary fibers encompass a biochemically diverse family of carbohydrates, and it remains unknown how different fiber sources influence immunity. In a head-to-head comparison of four different high-fiber diets, we demonstrate a unique and potent ability of guar gum to reduce neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a T cell-mediated mouse model of multiple sclerosis. CD4+ T cells from guar gum-fed mice have blunted Th1-skewing, reduced migratory capacity, and limited activation and proliferative capabilities. These changes are not explained by guar gum-specific alterations to the microbiota at the 16S rRNA level, nor by specific alterations in short chain fatty acids. These findings demonstrate specificity in the host response to fiber sources, and define a new pathway of fiber-induced CD4+ T cell immunomodulation that protects against pathologic neuroinflammation.

immunology↗

bioRxiv2020

STAT1-dependent tolerance of intestinal viral infection

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that maintain tolerance to the virome remain largely unknown. Here, we use colonization with the model commensal murine norovirus (MNV CR6) to interrogate host-directed mechanisms of viral tolerance, and show that STAT1 is a central coordinator of tolerance following CR6 colonization. STAT1 restricts CR6 replication to the intestinal tract, prevents systemic viral-induced tissue damage and disease, and regulates antiviral CD4+ and CD8+ T cell responses. In contrast to systemic viral pathogens that drive T cell mediated immunopathology in STAT1-deficient mice, our data indicates that loss of CD4+ or CD8+ T cells and their associated effector functions has no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound to limit viral replication prevented viral-induced tissue damage and death despite ongoing dysregulated antiviral T cell responses. Collectively, our data uncouple the requirement for STAT1-mediated regulation of antiviral T cell responses from innate immune-mediated restriction of viral replication that is necessary for intestinal viral tolerance.

immunology↗