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      Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease.

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          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.

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          Author and article information

          Journal
          J. Virol.
          Journal of virology
          1098-5514
          0022-538X
          Jan 2016
          : 90
          : 1
          Affiliations
          [1 ] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
          [2 ] 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.
          [3 ] Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
          [4 ] Transgenic Mouse Core Facility, Institute for Translational Sciences and Animal Resource Center, University of Texas Medical Branch, Galveston, Texas, USA.
          [5 ] Institute of Medical Microbiology, Fudan University, Shanghai, China.
          [6 ] Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA.
          [7 ] Department of Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch, Galveston, Texas, USA.
          [8 ] 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.
          Article
          JVI.02009-15
          10.1128/JVI.02009-15
          26446606
          Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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