Segmented filamentous bacteria confer protection against norovirus infection through enhanced viral clearance, immune modulation, and intestinal barrier function

Segmented filamentous bacteria (SFB) colonization confers robust, multi-faceted protection against norovirus infection. Using germ-free (GF), SFB-monoassociated, and control bacteria-monoassociated mouse models infected with murine norovirus (MNV), we demonstrate that SFB profoundly accelerates viral clearance. SFB-colonized mice exhibited significantly reduced fecal viral loads by day 5 post-infection (dpi) compared to GF and control bacteria mice (p < 0.001), reaching near-baseline levels by day 10. This enhanced viral control correlated with markedly attenuated morbidity; SFB mice experienced minimal weight loss and rapid recovery, while GF and control mice suffered severe weight loss and delayed recovery (p < 0.001). At peak infection (3 dpi), SFB colonization significantly suppressed viral replication in feces and tissues and attenuated intestinal pathology. SFB also preserved barrier integrity, evidenced by reduced serum FITC-dextran. Mechanistically, SFB induced a distinctive antiviral cytokine profile, characterized by elevated IFN-λ and IL-22, while tempering IFN-γ increases. Protection was dose-dependent, with pre-infection SFB abundance strongly inversely correlating with day 3 viral load and pathology. Integrated multi-parameter and principal component analyses revealed a unique SFB-driven protective state, featuring accelerated clearance, reduced pathology/inflammation, barrier preservation, and elevated protective cytokines, establishing a pre-primed mucosal environment. Thus, SFB orchestrates comprehensive defense against norovirus through enhanced viral clearance, immunomodulation, and barrier fortification.