Human metapneumovirus glycoprotein G inhibits innate immune responses.
Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infection in infants, as well as in the elderly and immunocompromised patients. No effective treatment or vaccine for hMPV is currently available. A recombinant hMPV lacking the G protein (rhMPV-Delta G) was recently developed as a potential vaccine candidate and shown to be attenuated in the respiratory tract of a rodent model of infection. The mechanism of its attenuation, as well as the role of G protein in modulation of hMPV-induced cellular responses in vitro, as well as in vivo, is currently unknown. In this study, we found that rhMPV-Delta G-infected airway epithelial cells produced higher levels of chemokines and type I interferon (IFN) compared to cells infected with rhMPV-WT. Infection of airway epithelial cells with rhMPV-Delta G enhanced activation of transcription factors belonging to the nuclear factor (NF)-kappaB and interferon regulatory factor (IRF) families, as revealed by increased nuclear translocation and/or phosphorylation of these transcription factors. Compared to rhMPV-WT, rhMPV-Delta G also increased IRF- and NF-kappaB-dependent gene transcription, which was reversely inhibited by G protein expression. Since RNA helicases have been shown to play a fundamental role in initiating viral-induced cellular signaling, we investigated whether retinoic induced gene (RIG)-I was the target of G protein inhibitory activity. We found that indeed G protein associated with RIG-I and inhibited RIG-I-dependent gene transcription, identifying an important mechanism by which hMPV affects innate immune responses. This is the first study investigating the role of hMPV G protein in cellular signaling and identifies G as an important virulence factor, as it inhibits the production of important immune and antiviral mediators by targeting RIG-I, a major intracellular viral RNA sensor.
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.
Xiaoyong
X
Bao
Tianshuang
T
Liu
Yichu
Y
Shan
Kui
K
Li
Roberto P
RP
Garofalo
Antonella
A
Casola
D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007109:Immunity; D007111:Immunity, Cellular; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D007370:Interferon Type I / Q000378:metabolism; D029121:Metapneumovirus / Q000472:pathogenicity / Q000502:physiology*; D016328:NF-kappa B / Q000096:biosynthesis; D018184:Paramyxoviridae Infections / Q000276:immunology*; D012367:RNA, Viral; D011971:Receptors, Immunologic; D020545:Respiratory Mucosa / Q000276:immunology / Q000821:virology; D015398:Signal Transduction; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D037521:Virulence Factors
D018925:Chemokines; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D016328:NF-kappa B; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014759:Viral Envelope Proteins; D037521:Virulence Factors; C116204:attachment protein G; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases