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

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.

Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines

“…The wild type RBD vaccine was used as a control. The animal model for vaccine testing was the lethal transgenic mouse model expressing human DPP4 (hDPP4-Tg mice)4142. These mice were chosen for analysis because they are very susceptible to MERS-CoV and also because preventing disease in these mice is a stringent test of efficacy.…”

“…MERS-CoV challenge studies were carried out using human-DPP4-transgenic mice as previously described41. Briefly, mice were intramuscularly immunized with wild type or mutant MERS-CoV RBD (5 μg per mouse) in the presence of aluminium adjuvant49, and boosted once 4 weeks after the initial immunization.…”

MERS-CoV spike protein: Targets for vaccines and therapeutics

“…In the second model, transgenic mice globally expressing hCD26 were generated by microinjection by two independent groups Zhao et al, 2015). When challenged with an overwhelming dose of MERS-CoV, the transgenic mice generated by Agrawal et al develop severe pneumonia, leading to death in 4e6 days.…”

Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection

“…Viral titer was detected as described (Zhao et al, 2015). Briefly, mouse lung tissues were homogenized in DMEM plus antibiotics to achieve 10% (w/v) suspensions, which were then titrated on monolayers of Vero cells in quadruplicate.…”