title: Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections.
abstract: 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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yun-Gi
authors.initials: YG
authors.lastname: Kim
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Park
authors.forename: Thornik
authors.initials: T
authors.lastname: Reimer
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Himanshu
authors.initials: H
authors.lastname: Kumar
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Christiane
authors.initials: C
authors.lastname: Wobus
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D017250:Caliciviridae Infections / Q000150:complications* / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004926:Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000401:mortality*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D029322:Norovirus / Q000502:physiology; D011070:Poly I-C / Q000276:immunology; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011070:Poly I-C