Immunomodulation of Host Immunity by Bacteriodes fragillis Polysaccharide A (PSA) Prevents Viral Encephalitis

Abstract

A major impact of commensal microbiota on many aspects of host physiology including regulation of host immunity extends beyond the gut to remote sites, including the brain. Studies in mouse models have shown that the commensal Bacteroides fragilis and its capsular PSA can prevent various inflammatory disorders including colitis, experimental autoimmune encephalomyelitis and asthma. However, little is known about the interaction of gut bacteria and their products with the immune system during viral infection. We assessed the immunomodulatory potential of PSA in a murine model of herpes simplex virus (HSV) encephalitis (HSE). Fatal HSE results from inflammation of the brain in susceptible 129 strain of mice due to uncontrolled invasion by Ly6C^(high) inflammatory monocytes (IM) and neutrophils. Naïve 129 mice pretreated with PSA or PBS were then given a 1-week course of the anti-viral drug acyclovir (ACV) from day 4-post HSV infection to simulate a clinical setting. PSA, but not PBS-treated mice survived with dramatically reduced brain inflammation including fewer degranulating IM and altered cytokine and chemokine profiles. Mesenteric lymph node cellularity was increased and IL-10 secreting ICOS^+ CD73^+ CD4^+ T cells and CD73^+ CD8^+ T cells were induced by PSA treatment. Importantly, IL-10 deficient and Rag knockout mice were not protected, suggesting T/B cells derived IL-10 as the protective mechanism. Interestingly, B cells were required for PSA mediated protection. We infer that the microbiota augment immunity to HSV using pathways distinct from those required for protection in chronic autoimmunity models, and that probiotics in combination with antivirals might act synergistically to limit HSV induced inflammatory diseases.

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