Development of a Mouse-Adapted MERS Coronavirus

Area of Science:

• Virology and Infectious Diseases
• Animal Models for Human Diseases
• Respiratory Pathogens

Background:

• Middle East respiratory syndrome coronavirus (MERS-CoV), identified in 2012, causes severe respiratory illness with a high fatality rate (~35%).
• Existing mouse models are resistant to MERS-CoV infection due to differences in the dipeptidyl peptidase 4 (DPP4) receptor.
• A functional animal model is crucial for understanding MERS-CoV pathogenesis and developing effective treatments and vaccines.

Purpose of the Study:

• To generate a mouse model that recapitulates severe lung disease and mortality associated with MERS-CoV infection.
• To adapt MERS-CoV for efficient replication and pathogenesis in a mammalian host.
• To provide a platform for evaluating MERS-CoV therapeutics and vaccines.

Main Methods:

• Generation of human DPP4 knock-in (hDPP4 KI) mice by replacing mouse Dpp4 exons with human counterparts.
• Serial in vivo passage of the MERS-CoV (HCoV-EMC/2012 strain) in the lungs of young hDPP4 KI mice.
• Isolation and characterization of an adapted MERS-CoV clone (MERS_MA6.1.2) exhibiting enhanced virulence.

Main Results:

• hDPP4 KI mice were susceptible to MERS-CoV infection but initially showed no disease.
• Serial lung passages led to the isolation of MERS_MA6.1.2, a highly adapted MERS-CoV clone.
• MERS_MA6.1.2 induced significant lung injury, high viral titers, and fatal respiratory disease in hDPP4 KI mice.

Conclusions:

• The serial passage method successfully adapted MERS-CoV to cause severe, lethal respiratory disease in hDPP4 KI mice.
• The MERS_MA6.1.2 clone represents a valuable tool for studying MERS-CoV pathogenesis.
• This novel mouse model provides a critical resource for preclinical testing of MERS-CoV interventions.