title: A mouse model for MERS coronavirus-induced acute respiratory distress syndrome.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR-Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Cockrell
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Yount
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Scobey
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Madeline
authors.initials: M
authors.lastname: Douglas
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Beall
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA.
authors.forename: Xian-Chun
authors.initials: XC
authors.lastname: Tang
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
authors.affiliation: Departments of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Departments of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Departments of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
mesh_terms: D000818:Animals; D018352:Coronavirus Infections / Q000150:complications*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D000072669:Gene Editing; D051379:Mice; D065207:Middle East Respiratory Syndrome Coronavirus / Q000254:growth & development*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D030781:Organisms, Genetically Modified; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D012128:Respiratory Distress Syndrome / Q000473:pathology*
chemical_list: D050505:Mutant Proteins; D011991:Receptors, Virus; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse