Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease

Area of Science:

• Virology
• Pathology
• Genetics

Background:

• A previously established mouse model (288-330^+/+) developed severe respiratory disease after infection with a high dose of mouse-adapted MERS-CoV (icMERSma1).
• Achieving similar pathology at lower viral doses is critical for better reflecting naturally acquired infections.

Purpose of the Study:

• To generate a novel mouse-adapted MERS-CoV (maM35c4) capable of causing severe respiratory disease at significantly lower viral doses.
• To identify specific mutations responsible for reduced viral dose pathogenicity.

Main Methods:

• Continued adaptive evolution of icMERSma1 to generate maM35c4.
• Comparative genetic analysis of icMERSma1 and maM35c4.
• Infection studies using varying viral doses (10³ to 10⁵ PFU) to assess respiratory disease severity.

Main Results:

• The novel maM35c4 strain caused severe respiratory disease at 10-1000 fold lower viral doses compared to icMERSma1.
• Specific novel mutations were identified in maM35c4, potentially responsible for enhanced pathogenicity at lower doses.
• Key mutations remained fixed through 20 additional cycles of adaptive evolution, indicating their stability and importance.

Conclusions:

• The extent of MERS-CoV adaptation directly influences the minimal infectious dose required for severe respiratory disease.
• Specific genetic mutations acquired during adaptive evolution are critical for increased MERS-CoV virulence and infectivity at lower doses.