Multi-Organ Damage in Human Dipeptidyl Peptidase 4 Transgenic Mice Infected with Middle East Respiratory Syndrome-Coronavirus

PLoS One. 2015 Dec 23;10(12):e0145561. doi: 10.1371/journal.pone.0145561. eCollection 2015.

Abstract

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokines / metabolism
  • Coronavirus Infections / complications*
  • Coronavirus Infections / virology
  • Cytokines / metabolism
  • Dipeptidyl Peptidase 4 / physiology*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle East Respiratory Syndrome Coronavirus / pathogenicity*
  • Multiple Organ Failure / etiology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Chemokines
  • Cytokines
  • RNA, Messenger
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse

Grant support

This work was supported by the National Project of Infectious Disease (2014ZX10004001004, 2012ZX10004502), the Basic Research 973 Project (2011CB504706), and the National Natural Science Foundation of China (81371805). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.