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Genetically Engineering a Susceptible Mouse Model for MERS-CoV-Induced Acute Respiratory Distress Syndrome
Sarah R Leist1, Adam S Cockrell2
1Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Since 2012, monthly cases of Middle East respiratory syndrome coronavirus (MERS-CoV) continue to cause severe respiratory disease that is fatal in ~35% of diagnosed individuals. The ongoing threat to global public health and the need for novel therapeutic countermeasures have driven the development of animal models that can reproducibly replicate the pathology associated with MERS-CoV in human infections. The inability of MERS-CoV to replicate in the respiratory tracts of mice, hamsters, and ferrets stymied initial attempts to generate small animal models. Identification of human dipeptidyl peptidase IV (hDPP4) as the receptor for MERS-CoV infection opened the door for genetic engineering of mice. Precise molecular engineering of mouse DPP4 (mDPP4) with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology maintained inherent expression profiles, and limited MERS-CoV susceptibility to tissues that naturally express mDPP4, notably the lower respiratory tract wherein MERS-CoV elicits severe pulmonary pathology. Here, we describe the generation of the 288-330+/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330), and the use of adaptive evolution to generate novel MERS-CoV isolates that cause fatal respiratory disease. The 288-330+/+ mice are currently being used to evaluate novel drug, antibody, and vaccine therapeutic countermeasures for MERS-CoV. The chapter starts with a historical perspective on the emergence of MERS-CoV and animal models evaluated for MERS-CoV pathogenesis, and then outlines the development of the 288-330+/+ mouse model, assays for assessing a MERS-CoV pulmonary infection in a mouse model, and describes some of the challenges associated with using genetically engineered mice.
Insights
Researchers developed a new mouse model for Middle East respiratory syndrome coronavirus (MERS-CoV) by genetically engineering mice to be susceptible to the virus. This MERS-CoV mouse model is crucial for testing new drugs and vaccines against the deadly respiratory disease.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe, often fatal, respiratory illness with a ~35% mortality rate.
- Existing small animal models failed to replicate MERS-CoV pathology due to limited viral replication in respiratory tracts.
- The identification of human dipeptidyl peptidase IV (hDPP4) as the MERS-CoV receptor was key to developing susceptible animal models.
Purpose of the Study:
- To develop a small animal model that accurately replicates MERS-CoV-induced pulmonary pathology.
- To create a platform for evaluating therapeutic countermeasures, including drugs, antibodies, and vaccines, against MERS-CoV.
- To engineer mice susceptible to MERS-CoV infection, specifically targeting the lower respiratory tract.
Main Methods:
- Genetic engineering of mouse dipeptidyl peptidase IV (mDPP4) using CRISPR/Cas9 technology to create the 288-330+/+ MERS-CoV mouse model.
- Modification of two key amino acids (A288 and T330) in mDPP4 to confer MERS-CoV susceptibility.
- Utilizing adaptive evolution to generate novel MERS-CoV isolates that induce fatal respiratory disease in the engineered mice.
Main Results:
- Successful generation of the 288-330+/+ MERS-CoV mouse model exhibiting susceptibility to MERS-CoV infection.
- The engineered mice display severe pulmonary pathology consistent with human MERS-CoV infections.
- The model allows for reproducible assessment of MERS-CoV infection in the lower respiratory tract.
Conclusions:
- The 288-330+/+ MERS-CoV mouse model provides a vital tool for preclinical evaluation of MERS-CoV therapeutics.
- This genetically engineered model overcomes limitations of previous animal models, enabling better understanding of MERS-CoV pathogenesis.
- Ongoing research utilizes this model to accelerate the development of effective treatments and preventative strategies for MERS-CoV.
