Secreted chorismate mutase: A novel prognostic factor in Mycobacterium intracellulare pulmonary disease.

Abstract

Objectives: Secreted chorismate mutase (S-CM) is known to act as a virulence factor in mycobacterial infections by inhibiting macrophage apoptosis. This study aims to investigate genetic variations in S-CM among Mycobacterium intracellulare strains and evaluate their influence on the clinical progression of M. intracellulare-pulmonary disease (PD).

Methods: Patients diagnosed with M. intracellulare-PD who received treatment between January 1, 2020, and December 31, 2023, at Seoul National University Hospital were included. Clinical isolates collected at treatment initiation were assessed for subspecies classification and S-CM genetic variations. Treatment outcomes were analyzed based on subspecies and S-CM mutation status. J774A.1 murine macrophages were infected with type strains (ATCC13950T) carrying S-CM expression plasmids and clinical isolates. Macrophage apoptosis and bacterial colony-forming units (CFUs) were quantified.

Results: Among the 118 isolates, 57 were identified as M. intracellulare subspecies intracellulare (Typical M. intracellulare, TMI), 53 as M. paraintracellulare, and eight as other subspecies. A C276A mutation causing S-CM truncation was detected in 24 isolates (20.3%), all belonging to TMI. TMI strains with S-CM truncation demonstrated a higher rate of culture conversion than those with intact S-CM (adjusted hazard ratio: 2.17, 95% confidence interval: 1.08-4.34, P = 0.029). In murine macrophages, TMI strains with truncated S-CM induced higher levels of apoptosis and lower CFUs, whereas expressing intact S-CM in a type strain with naturally truncated S-CM reduced apoptosis and increased bacterial burden.

Conclusions: S-CM truncation in M. intracellulare enhances macrophage apoptosis, yielding reduced bacterial burden, decreased pathogenicity, and improved treatment responses.