Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment.
The high mortality associated with the novel Middle East respiratory syndrome coronavirus (MERS-CoV) has raised questions about the possible role of a cytokine storm in its pathogenesis. Although recent studies showed that MERS-CoV infection is associated with an attenuated IFN response, no induction of inflammatory cytokines was demonstrated during the early phase of infection. To study both early and late cytokine responses associated with MERS-CoV infection, we measured the mRNA levels of eight cytokine genes [TNF-α, IL-1β, IL-6, IL-8, IFN-β, monocyte chemotactic protein-1, transforming growth factor-β and IFN-γ-induced protein (IP)-10] in cell lysates of polarized airway epithelial Calu-3 cells infected with MERS-CoV or severe acute respiratory syndrome (SARS)-CoV up to 30 h post-infection. Among the eight cytokine genes, IL-1β, IL-6 and IL-8 induced by MERS-CoV were markedly higher than those induced by SARS-CoV at 30 h, whilst TNF-α, IFN-β and IP-10 induced by SARS-CoV were markedly higher than those induced by MERS-CoV at 24 and 30 h in infected Calu-3 cells. The activation of IL-8 and attenuated IFN-β response by MERS-CoV were also confirmed by protein measurements in the culture supernatant when compared with SARS-CoV and Sendai virus. To further confirm the attenuated antiviral response, cytokine response was compared with human HCoV-229E in embryonal lung fibroblast HFL cells, which also revealed higher IFN-β and IP-10 levels induced by HCoV-229E than MERS-CoV at 24 and 30 h. Whilst our data supported recent findings that MERS-CoV elicits attenuated innate immunity, this represents the first report to demonstrate delayed proinflammatory cytokine induction by MERS-CoV. Our results provide insights into the pathogenesis and treatment of MERS-CoV infections.
Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.|State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, P.R. China.|Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, P.R. China.|Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, P.R. China.
Susanna K P
SKP
Lau
Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.
Candy C Y
CCY
Lau
Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.
Kwok-Hung
KH
Chan
Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.
Clara P Y
CPY
Li
Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, P.R. China.|Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, P.R. China.|State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, P.R. China.|Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.
Honglin
H
Chen
Department of Biochemistry, University of Hong Kong, Hong Kong, P.R. China.
Dong-Yan
DY
Jin
Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.
Jasper F W
JFW
Chan
Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, P.R. China.|Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.|State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, P.R. China.|Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, P.R. China.
Patrick C Y
PCY
Woo
State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, P.R. China.|Department of Microbiology, University of Hong Kong, Hong Kong, P.R. China.|Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, P.R. China.|Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, P.R. China.
Kwok-Yung
KY
Yuen
D001980:Bronchi / Q000166:cytology / Q000821:virology; D002460:Cell Line; D017934:Coronavirus / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008877:Middle East; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology / Q000628:therapy*; D019562:Viral Load; D014779:Virus Replication
D016207:Cytokines