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Proc Natl Acad Sci USA. Rapid generation of a mouse model for Middle East respiratory syndrome
[Source: Proceeding of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
Rapid generation of a mouse model for Middle East respiratory syndrome
Jincun Zhao<SUP>a</SUP>, Kun Li<SUP>b</SUP>, Christine Wohlford-Lenane<SUP>b</SUP>, Sudhakar S. Agnihothram<SUP>c</SUP>, Craig Fett<SUP>a</SUP>, Jingxian Zhao<SUP>a</SUP>, Michael J. Gale, Jr.<SUP>d</SUP>, Ralph S. Baric<SUP>c</SUP>, Luis Enjuanes<SUP>e</SUP>, Tom Gallagher<SUP>f</SUP>, Paul B. McCray, Jr.<SUP>b</SUP>, and Stanley Perlman<SUP>a</SUP>,<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: Departments of <SUP>a</SUP>Microbiology and <SUP>b</SUP>Pediatrics, University of Iowa, Iowa City, IA 52240; <SUP>c</SUP>Departments of Microbiology and Immunology and of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; <SUP>d</SUP>Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109; <SUP>e</SUP>Department of Molecular and Cell Biology, Centro Nacional de Biotecnolog?a-Consejo Superior de Investigaciones Cient?ficas, Campus Universidad Aut?noma de Madrid, Cantoblanco, 28049 Madrid, Spain; and <SUP>f</SUP>Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, IL 60153
Edited by Michael B. A. Oldstone, The Scripps Research Institute, La Jolla, CA, and approved February 21, 2014 (received for review December 16, 2013)
Abstract
Significance
The Middle East respiratory syndrome (MERS)-coronavirus, a newly identified pathogen, causes severe pneumonia in humans, with a mortality of nearly 44%. Human-to-human spread has been demonstrated, raising the possibility that the infection could become pandemic. Mice and other small laboratory animals are not susceptible to infection. Here, we describe the development of a small-animal model for MERS, in which we use an adenovirus expressing the human host-cell receptor to sensitize mice for infection. We show that these mice are useful for determining immune responses and for evaluation of an anti-MERS vaccine and an antiviral therapy. This approach will be generally useful for the rapid (2?3 wk) development of relevant mouse and other animal models for emerging viral infections.
Abstract
In this era of continued emergence of zoonotic virus infections, the rapid development of rodent models represents a critical barrier to public health preparedness, including the testing of antivirus therapy and vaccines. The Middle East respiratory syndrome coronavirus (MERS-CoV) was recently identified as the causative agent of a severe pneumonia. Given the ability of coronavirus to rapidly adapt to new hosts, a major public health concern is that MERS-CoV will further adapt to replication in humans, triggering a pandemic. No small-animal model for this infection is currently available, but studies suggest that virus entry factors can confer virus susceptibility. Here, we show that mice were sensitized to MERS-CoV infection by prior transduction with adenoviral vectors expressing the human host-cell receptor dipeptidyl peptidase 4. Mice developed a pneumonia characterized by extensive inflammatory-cell infiltration with virus clearance occurring 6?8 d after infection. Clinical disease and histopathological changes were more severe in the absence of type-I IFN signaling whereas the T-cell response was required for virus clearance. Using these mice, we demonstrated the efficacy of a therapeutic intervention (poly I:C) and a potential vaccine [Venezuelan equine encephalitis replicon particles expressing MERS-CoV spike protein]. We also found little protective cross-reactivity between MERS-CoV and the severe acute respiratory syndrome-CoV. Our results demonstrate that this system will be useful for MERS-CoV studies and for the rapid development of relevant animal models for emerging respiratory viral infections.
emerging pathogen ? interferon ? SARS
Footnotes
<SUP>1</SUP>To whom correspondence should be addressed. E-mail: stanley-perlman@uiowa.edu.
Author contributions: Jincun Zhao, T.G., P.B.M., and S.P. designed research; Jincun Zhao, K.L., C.W.-L., C.F., and Jingxian Zhao performed research; S.S.A., M.J.G., R.S.B., and L.E. contributed new reagents/analytic tools; Jincun Zhao, K.L., C.W.-L., Jingxian Zhao, P.B.M., and S.P. analyzed data; and Jincun Zhao, T.G., P.B.M., and S.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1323279111/-/DCSupplemental.
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Rapid generation of a mouse model for Middle East respiratory syndrome
Jincun Zhao<SUP>a</SUP>, Kun Li<SUP>b</SUP>, Christine Wohlford-Lenane<SUP>b</SUP>, Sudhakar S. Agnihothram<SUP>c</SUP>, Craig Fett<SUP>a</SUP>, Jingxian Zhao<SUP>a</SUP>, Michael J. Gale, Jr.<SUP>d</SUP>, Ralph S. Baric<SUP>c</SUP>, Luis Enjuanes<SUP>e</SUP>, Tom Gallagher<SUP>f</SUP>, Paul B. McCray, Jr.<SUP>b</SUP>, and Stanley Perlman<SUP>a</SUP>,<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: Departments of <SUP>a</SUP>Microbiology and <SUP>b</SUP>Pediatrics, University of Iowa, Iowa City, IA 52240; <SUP>c</SUP>Departments of Microbiology and Immunology and of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; <SUP>d</SUP>Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109; <SUP>e</SUP>Department of Molecular and Cell Biology, Centro Nacional de Biotecnolog?a-Consejo Superior de Investigaciones Cient?ficas, Campus Universidad Aut?noma de Madrid, Cantoblanco, 28049 Madrid, Spain; and <SUP>f</SUP>Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, IL 60153
Edited by Michael B. A. Oldstone, The Scripps Research Institute, La Jolla, CA, and approved February 21, 2014 (received for review December 16, 2013)
Abstract
Significance
The Middle East respiratory syndrome (MERS)-coronavirus, a newly identified pathogen, causes severe pneumonia in humans, with a mortality of nearly 44%. Human-to-human spread has been demonstrated, raising the possibility that the infection could become pandemic. Mice and other small laboratory animals are not susceptible to infection. Here, we describe the development of a small-animal model for MERS, in which we use an adenovirus expressing the human host-cell receptor to sensitize mice for infection. We show that these mice are useful for determining immune responses and for evaluation of an anti-MERS vaccine and an antiviral therapy. This approach will be generally useful for the rapid (2?3 wk) development of relevant mouse and other animal models for emerging viral infections.
Abstract
In this era of continued emergence of zoonotic virus infections, the rapid development of rodent models represents a critical barrier to public health preparedness, including the testing of antivirus therapy and vaccines. The Middle East respiratory syndrome coronavirus (MERS-CoV) was recently identified as the causative agent of a severe pneumonia. Given the ability of coronavirus to rapidly adapt to new hosts, a major public health concern is that MERS-CoV will further adapt to replication in humans, triggering a pandemic. No small-animal model for this infection is currently available, but studies suggest that virus entry factors can confer virus susceptibility. Here, we show that mice were sensitized to MERS-CoV infection by prior transduction with adenoviral vectors expressing the human host-cell receptor dipeptidyl peptidase 4. Mice developed a pneumonia characterized by extensive inflammatory-cell infiltration with virus clearance occurring 6?8 d after infection. Clinical disease and histopathological changes were more severe in the absence of type-I IFN signaling whereas the T-cell response was required for virus clearance. Using these mice, we demonstrated the efficacy of a therapeutic intervention (poly I:C) and a potential vaccine [Venezuelan equine encephalitis replicon particles expressing MERS-CoV spike protein]. We also found little protective cross-reactivity between MERS-CoV and the severe acute respiratory syndrome-CoV. Our results demonstrate that this system will be useful for MERS-CoV studies and for the rapid development of relevant animal models for emerging respiratory viral infections.
emerging pathogen ? interferon ? SARS
Footnotes
<SUP>1</SUP>To whom correspondence should be addressed. E-mail: stanley-perlman@uiowa.edu.
Author contributions: Jincun Zhao, T.G., P.B.M., and S.P. designed research; Jincun Zhao, K.L., C.W.-L., C.F., and Jingxian Zhao performed research; S.S.A., M.J.G., R.S.B., and L.E. contributed new reagents/analytic tools; Jincun Zhao, K.L., C.W.-L., Jingxian Zhao, P.B.M., and S.P. analyzed data; and Jincun Zhao, T.G., P.B.M., and S.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1323279111/-/DCSupplemental.
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