title: Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice.
abstract: The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ∼36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10-12 of the mouseDpp4locus. Upon inoculation with MERS-CoV, human DPP4 knockin (KI) mice supported virus replication in the lungs, but developed no illness. After 30 serial passages through the lungs of KI mice, a mouse-adapted virus emerged (MERSMA) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERSMAclone caused weight loss and fatal infection. Virus antigen was observed in airway epithelia, pneumocytes, and macrophages. Pathologic findings included diffuse alveolar damage with pulmonary edema and hyaline membrane formation associated with accumulation of activated inflammatory monocyte-macrophages and neutrophils in the lungs. Relative to the parental MERS-CoV, MERSMAviruses contained 13-22 mutations, including several within the spike (S) glycoprotein gene. S-protein mutations sensitized viruses to entry-activating serine proteases and conferred more rapid entry kinetics. Recombinant MERSMAbearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERSMAprovide tools to investigate disease causes and develop new therapies.
authors.affiliation: Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242.
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Wohlford-Lenane
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Rudragouda
authors.initials: R
authors.lastname: Channappanavar
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.
authors.forename: James T
authors.initials: JT
authors.lastname: Earnest
authors.affiliation: Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA 52242.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Bair
authors.affiliation: College of Dentistry, University of Iowa, Iowa City, IA 52242.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Bates
authors.affiliation: College of Dentistry, University of Iowa, Iowa City, IA 52242.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Brogden
authors.affiliation: Department of Veterinary Pathology, Iowa State University, Ames, IA 50011.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Flaherty
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.
authors.forename: Tom
authors.initials: T
authors.lastname: Gallagher
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242.|Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
authors.affiliation: Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242; paul-mccray@uiowa.edu.|Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
mesh_terms: D000818:Animals; D018352:Coronavirus Infections / Q000150:complications* / Q000821:virology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics*; D009154:Mutation; D064370:Spike Glycoprotein, Coronavirus / Q000235:genetics*; D014779:Virus Replication
chemical_list: D064370:Spike Glycoprotein, Coronavirus; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: CD26; emerging pathogen; interferon; spike protein; virus pathogenesis