Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Kun Li; Christine Wohlford-Lenane; Stanley Perlman; Jincun Zhao; Alexander K Jewell; Leah R Reznikov; Katherine N Gibson-Corley; David K Meyerholz; Paul B McCray Jr

doi:10.1093/infdis/jiv499

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Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Journal article

Open access

Peer reviewed

Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Kun Li, Christine Wohlford-Lenane, Stanley Perlman, Jincun Zhao, Alexander K Jewell, Leah R Reznikov, Katherine N Gibson-Corley, David K Meyerholz and Paul B McCray Jr

The Journal of infectious diseases, Vol.213(5), pp.712-722

03/01/2016

DOI: 10.1093/infdis/jiv499

PMCID: PMC4747621

PMID: 26486634

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Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes life-threatening disease. Dipeptidyl peptidase 4 (DPP4) is the receptor for cell binding and entry. There is a need for small-animal models of MERS, but mice are not susceptible to MERS because murine dpp4 does not serve as a receptor. We developed transgenic mice expressing human DPP4 (hDPP4) under the control of the surfactant protein C promoter or cytokeratin 18 promoter that are susceptible to infection with MERS-CoV. Notably, mice expressing hDPP4 with the cytokeratin 18 promoter developed progressive, uniformly fatal disease following intranasal inoculation. High virus titers were present in lung and brain tissues 2 and 6 days after infection, respectively. MERS-CoV-infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected. Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem. Animals immunized with a vaccine candidate were uniformly protected from lethal infection. These new mouse models of MERS-CoV should be useful for investigation of early disease mechanisms and therapeutic interventions.

Dipeptidyl Peptidase 4 - metabolism

Central Nervous System Viral Diseases - mortality

Humans

Dipeptidyl Peptidase 4 - genetics

Mice, Transgenic

Coronavirus Infections - mortality

Gene Expression Regulation, Enzymologic

Central Nervous System Viral Diseases - virology

Animals

Coronavirus Infections - virology

Coronavirus Infections - pathology

Central Nervous System Viral Diseases - pathology

Mice

RNA, Viral - isolation & purification

Middle East Respiratory Syndrome Coronavirus - physiology

Details

Title: Subtitle: Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4
Creators: Kun Li - Department of Pediatrics
Christine Wohlford-Lenane - Department of Pediatrics
Stanley Perlman - Department of Pediatrics Department of Microbiology Interdisciplinary Program in Immunology, University of Iowa, Iowa City
Jincun Zhao - Department of Microbiology
Alexander K Jewell - Department of Pediatrics
Leah R Reznikov - University of Iowa
Katherine N Gibson-Corley - Department of Pathology
David K Meyerholz - Department of Pathology
Paul B McCray Jr - Department of Pediatrics Department of Microbiology
Resource Type: Journal article
Publication Details: The Journal of infectious diseases, Vol.213(5), pp.712-722
DOI: 10.1093/infdis/jiv499
PMID: 26486634
PMCID: PMC4747621
NLM abbreviation: J Infect Dis
ISSN: 1537-6613
eISSN: 1537-6613
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS P30 DK-54759 / NIDDK NIH HHS P01 AI060699 / NIAID NIH HHS P30 DK054759 / NIDDK NIH HHS K99 HL119560 / NHLBI NIH HHS
Language: English
Date published: 03/01/2016
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics); Ophthalmology and Visual Sciences
Record Identifier: 9983777474602771

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