title: Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease.
abstract: Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID50) and lethal dose (LD50) of virus were estimated to be <1 and 10 TCID50 of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID50/LD50 determinations, and all were fully immune to challenge with 100 LD50 of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD50 of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10(5) LD50 of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research.
  
  
  OBJECTIVE
  Fully characterized animal models are essential for studying pathogenesis and for preclinical screening of vaccines and drugs against MERS-CoV infection and disease. When given a high dose of MERS-CoV, our transgenic mice expressing hCD26/DPP4 viral receptor uniformly succumbed to death within 6 days, making it difficult to evaluate host responses to infection and disease. We further characterized this model by determining both the ID50 and the LD50 of MERS-CoV in order to establish both an infection model and a lethal model for MERS and followed this by investigating the antibody responses and immunity of the mice that survived MERS-CoV infection. Using the estimated LD50 and ID50 data, we dissected the kinetics of viral tissue distribution and pathology in mice challenged with 10 LD50 of virus and utilized the model for preclinical evaluation of a vaccine and drug for treatment of MERS-CoV infection. This further-characterized transgenic mouse model will be useful for advancing MERS research.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Garron
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Anurodh Shankar
authors.initials: AS
authors.lastname: Agrawal
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Algaissi
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
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, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Teh-Sheng
authors.initials: TS
authors.lastname: Chan
authors.affiliation: Institute of Medical Microbiology, Fudan University, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA.
authors.forename: Lanying
authors.initials: L
authors.lastname: Du
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Couch
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch, Galveston, Texas, USA sktseng@utmb.edu.
authors.forename: Chien-Te K
authors.initials: CT
authors.lastname: Tseng
mesh_terms: D000825:Animal Structures / Q000473:pathology / Q000821:virology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage; D001921:Brain / Q000473:pathology / Q000821:virology; D018352:Coronavirus Infections / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control / Q000821:virology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006651:Histocytochemistry; D006801:Humans; D007928:Lethal Dose 50; D008099:Liver / Q000473:pathology / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D008822:Mice, Transgenic; D065207:Middle East Respiratory Syndrome Coronavirus / Q000254:growth & development* / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D014765:Viral Vaccines