The bacterium, nontypeable Haemophilus influenzae, enhances host antiviral response by inducing Toll-like receptor 7 expression: evidence for negative regulation of host anti-viral response by CYLD.
The incidence of mixed viral/bacterial infections has increased recently because of the dramatic increase in antibiotic-resistant strains, the emergence of new pathogens, and the resurgence of old ones. Despite the relatively well-known role of viruses in enhancing bacterial infections, the impact of bacterial infections on viral infections remains unknown. In this study, we provide direct evidence that nontypeable Haemophilus influenzae (NTHi), a major respiratory bacterial pathogen, augments the host antiviral response by up-regulating epithelial Toll-like receptor 7 (TLR7) expression in vitro and in vivo. Moreover, NTHi induces TLR7 expression via a TLR2-MyD88-IRAK-TRAF6-IKK-NF-kappaB-dependent signaling pathway. Interestingly, CYLD, a novel deubiquitinase, acts as a negative regulator of TLR7 induction by NTHi. Our study thus provides new insights into a novel role for bacterial infection in enhancing host antiviral response and further identifies CYLD for the first time as a critical negative regulator of host antiviral response.
Sakai
Akihiro
A
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Koga
Tomoaki
T
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Lim
Jae-Hyang
JH
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Jono
Hirofumi
H
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Harada
Kazutsune
K
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Szymanski
Erika
E
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Xu
Haidong
H
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Kai
Hirofumi
H
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
Li
Jian-Dong
JD
 Department of Microbiology & Immunology, University of Rochester Medical Center, NY, USA Gonda Department of Cell & Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA, USA Department of Molecular Medicine, Kumamoto University, Japan.
D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D006193:Haemophilus influenzae / Q000145:classification / Q000502:physiology*; D006801:Humans; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D016207:Cytokines; D008562:Membrane Glycoproteins; C495342:TLR2 protein, human; C495348:TLR7 protein, human; C493486:Tlr2 protein, mouse; C477038:Tlr7 protein, mouse; D051195:Toll-Like Receptor 2; D051199:Toll-Like Receptor 7; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases