Journal article
Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice
Proceedings of the National Academy of Sciences of the United States of America, Vol.114(15), pp.E3119-E3128
04/11/2017
DOI: 10.1073/pnas.1619109114
PMCID: PMC5393213
PMID: 28348219
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 mouse locus. 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 (MERS ) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERS clone 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, MERS viruses 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 MERS bearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERS provide tools to investigate disease causes and develop new therapies.
Details
- Title: Subtitle
- Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice
- Creators
- Kun Li - Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242Christine L Wohlford-Lenane - Department of Pediatrics, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242Rudragouda Channappanavar - Department of Microbiology, University of Iowa, Iowa City, IA 52242Jung-Eun Park - Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153James T Earnest - Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153Thomas B Bair - Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA 52242Amber M Bates - College of Dentistry, University of Iowa, Iowa City, IA 52242Kim A Brogden - College of Dentistry, University of Iowa, Iowa City, IA 52242Heather A Flaherty - Department of Veterinary Pathology, Iowa State University, Ames, IA 50011Tom Gallagher - Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, IA 52242Stanley Perlman - Department of Microbiology, University of Iowa, Iowa City, IA 52242Paul B McCray Jr - Department of Microbiology, University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences of the United States of America, Vol.114(15), pp.E3119-E3128
- DOI
- 10.1073/pnas.1619109114
- PMID
- 28348219
- PMCID
- PMC5393213
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- United States
- Grant note
- P01 AI060699 / NIAID NIH HHS P30 ES005605 / NIEHS NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 04/11/2017
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Dental Research; Infectious Disease (Pediatrics); Periodontics
- Record Identifier
- 9983777346102771
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