Viral Infection Augments Nod1/2 Signaling to Potentiate Lethality Associated with Secondary Bacterial Infections

SummarySecondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs Nod1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced Nod1 and Nod2 signaling by poly I:C required the TLR3/MDA5 adaptors TRIF and IPS-1 and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-β induced the expression of Nod1, Nod2, and the Nod-signaling adaptor Rip2. Systemic administration of poly I:C or IFN-β or infection with murine norovirus-1 promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden but attenuated in the absence of Nod1/Nod2 or Rip2. Thus, crosstalk between type I IFNs and Nod1/Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host.

► Viral infection augments Nod1 and Nod2 activation via the production of type I IFNs
► Type I IFN signaling induces expression of Nod1, Nod2, and Rip2
► Nod1/Nod2 potentiate susceptibility to bacterial infection in virally infected mice
► IFN-β enhances bacteria-induced lethality via Nod1 and Nod2