title: Rapid generation of a mouse model for Middle East respiratory syndrome.
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.
authors.affiliation: Departments of Microbiology and Pediatrics, University of Iowa, Iowa City, IA 52240.
authors.forename: Jincun
authors.initials: J
authors.lastname: Zhao
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.forename: Christine
authors.initials: C
authors.lastname: Wohlford-Lenane
authors.forename: Sudhakar S
authors.initials: SS
authors.lastname: Agnihothram
authors.forename: Craig
authors.initials: C
authors.lastname: Fett
authors.forename: Jingxian
authors.initials: J
authors.lastname: Zhao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gale
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
authors.forename: Luis
authors.initials: L
authors.lastname: Enjuanes
authors.forename: Tom
authors.initials: T
authors.lastname: Gallagher
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D017934:Coronavirus / Q000276:immunology / Q000502:physiology; D018352:Coronavirus Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology*; D003429:Cross Reactions / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008877:Middle East; D012141:Respiratory Tract Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology*; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D007370:Interferon Type I
keywords: SARS; emerging pathogen; interferon