Secreted Chorismate Mutase: A Novel Prognostic Factor in Mycobacterium intracellulare Pulmonary Disease.

Abstract

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). Patients diagnosed with M intracellulare PD who received treatment between 1 January 2020 and 31 December 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. Among the 118 isolates, 57 were identified as M intracellulare subspecies intracellulare (typical M intracellulare [TMI]), 53 as Mycobacterium paraintracellulare, and 8 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 = .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. S-CM truncation in M intracellulare enhances macrophage apoptosis, yielding reduced bacterial burden, decreased pathogenicity, and improved treatment responses.