title: Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease.
abstract: The emergence of Middle East respiratory syndrome-coronavirus (MERS-CoV) in the Middle East since 2012 has caused more than 900 human infections with ∼40% mortality to date. Animal models are needed for studying pathogenesis and for development of preventive and therapeutic agents against MERS-CoV infection. Nonhuman primates (rhesus macaques and marmosets) are expensive models of limited availability. Although a mouse lung infection model has been described using adenovirus vectors expressing human CD26/dipeptidyl peptidase 4 (DPP4), it is believed that a transgenic mouse model is needed for MERS-CoV research. We have developed this transgenic mouse model as indicated in this study. We show that transgenic mice globally expressing hCD26/DPP4 were fully permissive to MERS-CoV infection, resulting in relentless weight loss and death within days postinfection. High infectious virus titers were recovered primarily from the lungs and brains of mice at 2 and 4 days postinfection, respectively, whereas viral RNAs were also detected in the heart, spleen, and intestine, indicating a disseminating viral infection. Infected Tg(+) mice developed a progressive pneumonia, characterized by extensive inflammatory infiltration. In contrast, an inconsistent mild perivascular cuffing was the only pathological change associated with the infected brains. Moreover, infected Tg(+) mice were able to activate genes encoding for many antiviral and inflammatory mediators within the lungs and brains, coinciding with the high levels of viral replication. This new and unique transgenic mouse model will be useful for furthering knowledge of MERS pathogenesis and for the development of vaccine and treatments against MERS-CoV infection.
  
  
  OBJECTIVE
  Small and economical animal models are required for the controlled and extensive studies needed for elucidating pathogenesis and development of vaccines and antivirals against MERS. Mice are the most desirable small-animal species for this purpose because of availability and the existence of a thorough knowledge base, particularly of genetics and immunology. The standard small animals, mice, hamsters, and ferrets, all lack the functional MERS-CoV receptor and are not susceptible to infection. So, initial studies were done with nonhuman primates, expensive models of limited availability. A mouse lung infection model was described where a mouse adenovirus was used to transfect lung cells for receptor expression. Nevertheless, all generally agree that a transgenic mouse model expressing the DPP4 receptor is needed for MERS-CoV research. We have developed this transgenic mouse model as indicated in this study. This new and unique transgenic mouse model will be useful for furthering MERS research.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Anurodh Shankar
authors.initials: AS
authors.lastname: Agrawal
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Tania
authors.initials: T
authors.lastname: Garron
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Bi-Hung
authors.initials: BH
authors.lastname: Peng
authors.affiliation: Transgenic Mouse Core Facility, Institute for Translational Sciences and Animal Resource Center, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Teh-Sheng
authors.initials: TS
authors.lastname: Chan
authors.affiliation: Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Couch
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch, Galveston, Texas sktseng@utmb.edu.
authors.forename: Chien-Te K
authors.initials: CT
authors.lastname: Tseng
mesh_terms: D000825:Animal Structures / Q000821:virology; D000818:Animals; D018352:Coronavirus Infections / Q000473:pathology* / Q000821:virology*; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008822:Mice, Transgenic; D065207:Middle East Respiratory Syndrome Coronavirus / Q000502:physiology*; D013997:Time Factors; D019562:Viral Load
chemical_list: C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4