Genetic Variation/Evolution and Differential Host Responses Resulting from In-Patient Adaptation of Mycobacterium...

Area of Science:

• Microbiology
• Genomics
• Immunology

Background:

• The Mycobacterium avium complex (MAC) comprises nontuberculosis mycobacteria, primarily affecting immunocompromised individuals.
• Genetic variability within MAC strains is linked to diverse immune responses and infection outcomes.

Purpose of the Study:

• To investigate genomic alterations in M. avium isolates from single patients over time.
• To evaluate host immune responses to sequential clinical isolates of M. avium.

Main Methods:

• Pulsed-field gel electrophoresis and whole-genome sequencing of 40 MAC isolates from 15 patients.
• Analysis of sequential isolates from patients 4, 9, and 13 with multiple available isolates.
• Infection models using murine macrophages and mice to assess host-pathogen interactions.

Main Results:

• Significant sequence variation, including single-nucleotide polymorphisms (SNPs), was observed in M. avium isolates.
• Evidence suggests M. avium accumulates mutations at a high rate during persistent infections.
• Sequential M. avium isolates showed increased persistence and downregulated inflammatory cytokines in host models.
• Rapid genetic evolution of M. avium in chronically infected patients was demonstrated.

Conclusions:

• M. avium undergoes rapid genetic evolution during chronic infections.
• Evolving M. avium strains exhibit altered virulence properties and immune evasion mechanisms.
• Genomic plasticity of M. avium contributes to persistent infections and disease progression.