Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections

Cell Host Microbe. 2011 Jun 16;9(6):496-507. doi: 10.1016/j.chom.2011.05.006.


Secondary 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caliciviridae Infections / complications*
  • Caliciviridae Infections / genetics
  • Caliciviridae Infections / immunology*
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / immunology
  • Escherichia coli / physiology
  • Escherichia coli Infections / etiology
  • Escherichia coli Infections / genetics
  • Escherichia coli Infections / immunology*
  • Escherichia coli Infections / mortality*
  • Female
  • Humans
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nod1 Signaling Adaptor Protein / genetics
  • Nod1 Signaling Adaptor Protein / immunology*
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / immunology*
  • Norovirus / physiology
  • Poly I-C / immunology
  • Signal Transduction*


  • Cytokines
  • Nod1 Signaling Adaptor Protein
  • Nod2 Signaling Adaptor Protein
  • Poly I-C