Clinically relevant mutations in the PhoR sensor kinase of host-adapted Mycobacterium abscessus isolates impact response to acidic pH and virulence

Area of Science:

• Microbiology
• Infectious Diseases
• Molecular Biology

Background:

• Nontuberculous mycobacteria, particularly Mycobacterium abscessus, are increasingly causing difficult-to-treat pulmonary infections worldwide.
• Research into M. abscessus pathogenesis, diagnosis, and treatment lags behind that of Mycobacterium tuberculosis due to its recent recognition as a significant human pathogen.
• Understanding the molecular basis of M. abscessus virulence is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the role of the two-component regulator PhoPR in the pathogenicity of Mycobacterium abscessus.
• To elucidate the regulatory network controlled by PhoPR and its function during host-pathogen interactions.
• To determine how PhoPR contributes to M. abscessus survival and persistence in the context of human lung infections.

Main Methods:

• Analysis of evolutionary pressure on the PhoPR regulator in clinical isolates from human lung infections.
• Investigating the activation conditions of PhoPR, specifically its response to acidic pH.
• Identifying the set of genes regulated by PhoPR and assessing their role in host adaptation.
• Evaluating the impact of PhoPR activity on M. abscessus survival within macrophages.

Main Results:

• The PhoPR regulator is under significant evolutionary pressure, suggesting its importance in M. abscessus virulence during human infection.
• PhoPR is activated under acidic pH conditions, a common environment within host cells like macrophages.
• PhoPR controls a specific set of genes essential for M. abscessus adaptation to the host environment.
• Clinical isolates from chronic lung infections exhibit hyperactivated PhoPR, enhancing M. abscessus resistance to macrophage-mediated killing.

Conclusions:

• The PhoPR two-component system is a key virulence factor for Mycobacterium abscessus, particularly in the context of chronic pulmonary infections.
• PhoPR activation by acidic pH enables M. abscessus to evade host immune defenses, specifically macrophage killing.
• Targeting the PhoPR regulatory pathway presents a potential therapeutic strategy for combating difficult-to-treat M. abscessus infections.