Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection

Abstract

Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections.

Gut regulatory T cells mediate immunological tolerance inSalmonella-infected superspreader hosts by suppressing cytotoxic activity of T cells

“…We confirmed the transcriptome data by flow cytometry and immunofluorescence, where we could find foci in the colon with CD3 + cells releasing granzyme B and perforin. Surprisingly, neutralization of CD8 + T cells in STm superspreader mice depleted of Tregs was not enough to rescue the tolerogenic phenotype, which is the opposite of what has been described recently for viral infections (38). However, our results demonstrating increased cytotoxic CD4 + T cells in the guts of superspreader hosts in the absence of Tregs and CD8+ T cells are similar to previous studies showing that in the absence of CD8 + T cells, CD4 + T cells can acquire a cytotoxic phenotype (39) and anti-tumoral responses (40) (Reviewed in (41)).…”

Type I interferon remodels lysosome function and modifies intestinal epithelial defense

“…By selectively elevating the frequency of Stm entry into the cytosol, IFN-I signaling could promote pathogenesis even if cell death is, in part, a protective mechanism due to the increase in hyperinfectious bacteria that are released upon cell lysis. IFN-I's role in promoting Stm-infected IEC death may also negatively affect the integrity of the intestinal epithelial barrier, aiding pathogen dissemination (62). Our paper does not conclusively define the mechanism(s) of death in IFN-I-primed Stm-infected IECs and suggests that multiple pathways, including apoptosis and pyroptosis, may be active at the same time.…”

Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation.

“…Our data suggests dynamics in COVID-19 patients may be similar to those observed in cancer patients: BSI-causing organisms may translocate from the gut into the blood, potentially due to loss of gut barrier integrity, through virusinduced tissue damage rather than chemotherapy. Consistent with this possibility, soluble immune mediators such as TNFa and interferons produced during viral infections, including SARS-CoV-2, damage the intestinal epithelium to disrupt the gut barrier, especially when the inflammatory response is sustained as observed in patient with severe COVID-19 [41][42][43] .…”