title: Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus.
abstract: The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Kou
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065, United States of America.
authors.forename: Lanying
authors.initials: L
authors.lastname: Du
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Tan
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, 10065, United States of America.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, Shanghai, 200433, China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Shihui
authors.initials: S
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D018352:Coronavirus Infections / Q000150:complications* / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065207:Middle East Respiratory Syndrome Coronavirus / Q000472:pathogenicity*; D009102:Multiple Organ Failure / Q000209:etiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse