title: MERS coronavirus induces apoptosis in kidney and lung by upregulating Smad7 and FGF2.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) causes sporadic zoonotic disease and healthcare-associated outbreaks in human. MERS is often complicated by acute respiratory distress syndrome (ARDS) and multi-organ failure(1,2). The high incidence of renal failure in MERS is a unique clinical feature not often found in other human coronavirus infections(3,4). Whether MERS-CoV infects the kidney and how it triggers renal failure are not understood(5,6). Here, we demonstrated renal infection and apoptotic induction by MERS-CoV in human ex vivo organ culture and a nonhuman primate model. High-throughput analysis revealed that the cellular genes most significantly perturbed by MERS-CoV have previously been implicated in renal diseases. Furthermore, MERS-CoV induced apoptosis through upregulation of Smad7 and fibroblast growth factor 2 (FGF2) expression in both kidney and lung cells. Conversely, knockdown of Smad7 effectively inhibited MERS-CoV replication and protected cells from virus-induced cytopathic effects. We further demonstrated that hyperexpression of Smad7 or FGF2 induced a strong apoptotic response in kidney cells. Common marmosets infected by MERS-CoV developed ARDS and disseminated infection in kidneys and other organs. Smad7 and FGF2 expression were elevated in the lungs and kidneys of the infected animals. Our results provide insights into the pathogenesis of MERS-CoV and host targets for treatment.
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Man-Lung
authors: ML
authors: Yeung
authors: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Chaoyang District, Beijing, 100021, China.
authors: Yanfeng
authors: Y
authors: Yao
authors: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Lilong
authors: L
authors: Jia
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Jasper F W
authors: JF
authors: Chan
authors: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Kwok-Hung
authors: KH
authors: Chan
authors: Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Kwok-Fan
authors: KF
authors: Cheung
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Honglin
authors: http://orcid.org/0000-0001-5108-8338
authors: H
authors: Chen
authors: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Vincent K M
authors: VK
authors: Poon
authors: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Alan K L
authors: AK
authors: Tsang
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Kelvin K W
authors: KK
authors: To
authors: Department of Surgery, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Ming-Kwong
authors: MK
authors: Yiu
authors: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Jade L L
authors: JL
authors: Teng
authors: Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Hin
authors: H
authors: Chu
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Jie
authors: J
authors: Zhou
authors: Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Qing
authors: Q
authors: Zhang
authors: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Chaoyang District, Beijing, 100021, China.
authors: Wei
authors: W
authors: Deng
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Susanna K P
authors: SK
authors: Lau
authors: Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Johnson Y N
authors: JY
authors: Lau
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Patrick C Y
authors: PC
authors: Woo
authors: Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Tak-Mao
authors: TM
authors: Chan
authors: Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Susan
authors: S
authors: Yung
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Bo-Jian
authors: BJ
authors: Zheng
authors: Department of Biochemistry, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Dong-Yan
authors: http://orcid.org/0000-0002-2778-3530
authors: DY
authors: Jin
authors: Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|President's Office, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Peter W
authors: PW
authors: Mathieson
authors: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Chaoyang District, Beijing, 100021, China.
authors: Chuan
authors: C
authors: Qin
authors: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.|Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
authors: Kwok-Yung
authors: KY
authors: Yuen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002144:Callithrix; D018352:Coronavirus Infections / Q000473:pathology*; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D065207:Middle East Respiratory Syndrome Coronavirus / Q000472:pathogenicity*; D009924:Organ Culture Techniques; D051906:Smad7 Protein / Q000378:metabolism*
chemical_list: C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016222:Fibroblast Growth Factor 2