Title : Selective microbiota influence anti-viral immunity in the chronic clone-13 LCMV infection model
Abstract:
Recent research has shed led light on the important and versatile roles of the intestinal microbiome not least due to its immunomodulatory role in various human diseases including immunotherapies and viral infections like COVID-19.
However, due to its complexity both in humans as well as animal models raised in different animal houses it has been notoriously difficult to pinpoint the level by which the microbiome can impact chronic viral infections. Here, we addressed whether the microbiome influences anti-viral immunity in the chronic strain (clone-13) of the systemic cytopathic lymphocytic choriomeningitis virus (LCMV). To address this question, we infected germ-free mice as well as mice colonized with a limited microbial flora (OMM12) in gnotobiotic isolators with clone-13 LCMV and investigated the T cell response in comparison to SPF-infected animals. Surprisingly, the microbial status did marginally affect the cytotoxic CD8+ T cell response while CD4+ T cells were highly impacted by the microbiome. While germ-free mice lost moderately more weight than the SPF control group during the clone-13 infection, OMM12 mice showed a drastic increase in weight loss and higher expansion of adoptively transferred virus-specific TCR-transgenic and endogenous Th1 cells as well as increased cytokine secretion (GzmB, TNFα, IFNγ). Interestingly, this altered anti-viral immunity was especially pronounced in the small intestine, suggesting that virus-specific T cells may be directly regulated in the intestine. Transcriptional profiling and flow cytometry analysis of adoptively transferred virus-specific CD4+ T cells from SPF and OMM12-colonized mice revealed a diminished population of TFH-like cells in the spleen and an increased population with high cytotoxic and inflammatory potential in the small intestine of OMM12-colonized animals.
In summary, our study shows that specific microbial communities can have a strong impact on anti-viral immunity and immunopathology and that this response is primarily driven by microbiome effects on virus-specific T helper cells.
