title: Type I Interferons Triggered through the Toll-Like Receptor 3-TRIF Pathway Control Coxsackievirus A16 Infection in Young Mice.
abstract: Coxsackievirus A16 (CVA16) is one of the major etiological agents of hand, foot, and mouth disease (HFMD) in children. The host defense mechanisms against CVA16 infection remain almost entirely unknown. Unlike previous observations with enterovirus 71 (EV71) infection, here we show that gamma interferon (IFN-γ) or invariant NK T cell deficiency does not affect disease development or the survival of CVA16-infected mice. In contrast, type I interferon receptor deficiency resulted in the development of more severe disease in mice, and the mice had a lower survival rate than wild-type mice. Similarly, a deficiency of Toll-like receptor 3 (TLR3) and TRIF, but not other pattern recognition receptors, led to the decreased survival of CVA16-infected mice. TLR3-TRIF signaling was indispensable for the induction of type I interferons during CVA16 infection in mice and protected young mice from disease caused by the infection. In particular, TRIF-mediated immunity was critical for preventing CVA16 replication in the neuronal system before disease occurred. IFN-β treatment was also found to compensate for TRIF deficiency in mice and decreased the disease severity in and mortality of CVA16-infected mice. Altogether, type I interferons induced by TLR3-TRIF signaling mediate protective immunity against CVA16 infection. These findings may shed light on therapeutic strategies to combat HFMD caused by CVA16 infection.
  
  
  OBJECTIVE
  Hand, foot, and mouth disease (HFMD) is a major threat to public health in the Asia-Pacific region. Both CVA16 and EV71 are major pathogens that are responsible for HFMD. The majority of research efforts have focused on the more virulent EV71, but little has been done with CVA16. Thus far, host immune responses to CVA16 infection have not yet been elucidated. The present study discovered an initial molecular mechanism underlying host protective immunity against CVA16 infection, providing the first explanation for why CVA16 and EV71 cause different clinical outcomes upon infection of humans. Therefore, different therapeutic strategies should be developed to treat HFMD cases caused by these two viruses.
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Juhao
authors: J
authors: Yang
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Chunfu
authors: C
authors: Yang
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Nining
authors: N
authors: Guo
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Kai
authors: K
authors: Zhu
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Kaiming
authors: K
authors: Luo
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Na
authors: N
authors: Zhang
authors: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors: Hui
authors: H
authors: Zhao
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Ying
authors: Y
authors: Cui
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
authors: Lei
authors: L
authors: Chen
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
authors: Hongyang
authors: H
authors: Wang
authors: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
authors: Jun
authors: J
authors: Gu
authors: Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China.
authors: Baoxue
authors: B
authors: Ge
authors: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors: Cheng-Feng
authors: CF
authors: Qin
authors: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China qbleng@sibs.ac.cn.
authors: Qibin
authors: http://orcid.org/0000-0002-4768-1312
authors: Q
authors: Leng
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D003384:Coxsackievirus Infections / Q000188:drug therapy / Q000517:prevention & control*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D017931:DNA Primers; D007370:Interferon Type I; D016899:Interferon-beta; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse