TY - JOUR
T1 - Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections
AU - Kim, Yun Gi
AU - Park, Jong Hwan
AU - Reimer, Thornik
AU - Baker, Darren P.
AU - Kawai, Taro
AU - Kumar, Himanshu
AU - Akira, Shizuo
AU - Wobus, Christiane
AU - Núñez, Gabriel
N1 - Funding Information:
The authors are grateful to Richard Flavell for Nod2-deficient mice; Biogen for providing purified unmodified and PEGylated murine IFN-β, Joel Whitfield from the Cellular Immunology Core Facility of the University of Michigan Cancer Center for ELISA assays, and Sharon Koonse for animal husbandry. We are grateful to Michael Shaw and Grace Chen for critical review of the manuscript and Nick Lukacs, Adolfo Garcia-Sastre, Koichi Fukase, Mary O'Riordan, and Stephen Lory for reagents or bacterial/viral strains. This work was supported by NIH grant R01 DK61707. Y.-G.K. was supported by training funds from the University of Michigan Comprehensive Cancer Center. D.P.B. is employed by Biogen Idec. Biogen Idec provided unmodified and PEGylated murine IFN-β for these studies at no cost and did not provide funds for these studies, nor was Biogen Idec involved in the study design, data analysis, or any decisions relating to manuscript preparation or submission.
PY - 2011/6/16
Y1 - 2011/6/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chom.2011.05.006
DO - 10.1016/j.chom.2011.05.006
M3 - Article
C2 - 21669398
AN - SCOPUS:79958746242
SN - 1931-3128
VL - 9
SP - 496
EP - 507
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -