Deciphering the different Mycobacterium avium complex infections of HIV and non-HIV patients by bacterial GWAS and...

Pulmonary diseases caused by Mycobacterium avium complex (MAC) show species-specific epidemiology: M. avium predominates in HIV-positive patients, while M. intracellulare mainly affects immunocompetent hosts. This study aimed to elucidate the bacterial and host mechanisms underlying these differences.

We integrated clinical metagenomic next-generation sequencing (mNGS), k-mer-based bacterial genome-wide association study (GWAS) of clinical isolates, peripheral blood immunophenotyping of 175 patients, and mouse infection models with or without CD4 depletion.

K-mer GWAS identified lipid metabolism and transport genes (notably mce) enriched in isolates from hosts with different HIV statuses. Immunophenotyping showed that in HIV-negative patients, M. intracellulare infection elicited higher NKT cell frequencies than M. avium, a difference absent in HIV-positive hosts. In mice, anti-CD4^-/M. intracellulare infection showed steadily increasing bacterial burden with time (ρ = 0.824), whereas M. avium exhibited no such trend. Early after infection (weeks 1-2), anti-CD4^-/M. avium group had higher bacterial burden and NKT levels than anti-CD4^-/M. intracellulare, but by week 4 the pattern reversed (all p < 0.05). CD4 depletion eliminated species-specific differences in NKT activation, and at both weeks 2 (p < 0.05) and 4 post-infection (p > 0.05), the anti-CD4⁺/M. avium groups carried a higher bacterial burden than the anti-CD4⁺/M. intracellulare groups.

MAC species exhibit fundamentally divergent infection dynamics driven by differential NKT cell activation, likely shaped by species-specific lipid antigens. This lipid-NKT axis explains contrasting clinical patterns of M. avium and M. intracellulare and highlights a potential target for host-directed interventions.