title: 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.
abstract: 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.
authors.affiliation:  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.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sakai
authors.affiliation:  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.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation:  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.
authors.forename: Jae-Hyang
authors.initials: JH
authors.lastname: Lim
authors.affiliation:  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.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.affiliation:  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.
authors.forename: Kazutsune
authors.initials: K
authors.lastname: Harada
authors.affiliation:  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.
authors.forename: Erika
authors.initials: E
authors.lastname: Szymanski
authors.affiliation:  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.
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.affiliation:  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.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.affiliation:  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.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: 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
chemical_list: 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