Human metapneumovirus glycoprotein G inhibits innate immune responses

被引:96
作者
Bao, Xiaoyong [1 ]
Liu, Tianshuang [1 ]
Shan, Yichu [1 ]
Li, Kui [2 ]
Garofalo, Roberto P. [1 ,2 ,3 ]
Casola, Antonella [1 ,2 ,3 ]
机构
[1] Univ Texas Galveston, Med Branch, Galveston, TX 77550 USA
[2] Univ Texas Galveston, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA
[3] Univ Texas Galveston, Med Branch, Sealy Ctr Vaccine Dev, Galveston, TX 77550 USA
关键词
D O I
10.1371/journal.ppat.1000077
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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-DG) 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-DG enhanced activation of transcription factors belonging to the nuclear factor (NF)-kappa B and interferon regulatory factor (IRF) families, as revealed by increased nuclear translocation and/or phosphorylation of these transcription factors. Compared to rhMPV-WT, rhMPV-DG also increased IRF-and NF-kappa B-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.
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页数:12
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共 52 条
[1]   The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG-I- and TBK-1-directed interferon responses [J].
Alff, Peter J. ;
Gavrilovskaya, Irina N. ;
Gorbunova, Elena ;
Endriss, Karen ;
Chong, Yuson ;
Geimonen, Erika ;
Sen, Nandini ;
Reich, Nancy C. ;
Mackow, Erich R. .
JOURNAL OF VIROLOGY, 2006, 80 (19) :9676-9686
[2]   Human metapneumovirus persists in BALB/c mice despite the presence of neutralizing antibodies [J].
Alvarez, R ;
Harrod, KS ;
Shieh, WJ ;
Zaki, S ;
Tripp, RA .
JOURNAL OF VIROLOGY, 2004, 78 (24) :14003-14011
[3]   The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter [J].
Andrejeva, J ;
Childs, KS ;
Young, DF ;
Carlos, TS ;
Stock, N ;
Goodbourn, S ;
Randall, RE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (49) :17264-17269
[4]   Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125 [J].
Arimoto, Kei-ichiro ;
Takahashi, Hitoshi ;
Hishiki, Takayuki ;
Konishi, Hicleyuki ;
Fujita, Takashi ;
Shimotohno, Kunitada .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (18) :7500-7505
[5]   Respiratory syncytial virus deficient in soluble G protein induced an increased proinflammatory response in human lung epithelial cells [J].
Arnold, R ;
König, B ;
Werchau, H ;
König, W .
VIROLOGY, 2004, 330 (02) :384-397
[6]   On the role of IRF in host defense [J].
Barnes, B ;
Lubyova, B ;
Pitha, PM .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2002, 22 (01) :59-71
[7]   MDA-5 is cleaved in poliovirus-infected cells [J].
Barral, Paola M. ;
Morrison, Juliet M. ;
Drahos, Jennifer ;
Gupta, Pankaj ;
Sarkar, Devanand ;
Fisher, Paul B. ;
Racaniello, Vincent R. .
JOURNAL OF VIROLOGY, 2007, 81 (08) :3677-3684
[8]   THE I-KAPPA-B PROTEINS - MULTIFUNCTIONAL REGULATORS OF REL/NF-KAPPA-B TRANSCRIPTION FACTORS [J].
BEG, AA ;
BALDWIN, AS .
GENES & DEVELOPMENT, 1993, 7 (11) :2064-2070
[9]   Infection of nonhuman primates with recombinant human metapneumovirus lacking the SH, G, or M2-2 protein categorizes each as a nonessential accessory protein and identifies vaccine candidates [J].
Biacchesi, S ;
Pham, QN ;
Skiadopoulos, MH ;
Murphy, BR ;
Collins, PL ;
Buchholz, UJ .
JOURNAL OF VIROLOGY, 2005, 79 (19) :12608-12613
[10]   Recovery of human metapneumovirus from cDNA: optimization of growth in vitro and expression of additional genes [J].
Biacchesi, S ;
Skiadopoulos, MH ;
Tran, KC ;
Murphy, BR ;
Collins, PL ;
Buchholz, UJ .
VIROLOGY, 2004, 321 (02) :247-259