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Purpose <p>Pulmonary diseases caused by <i>Mycobacterium avium</i> complex (MAC) show species-specific epidemiology: <i>M. avium</i> predominates in HIV-positive patients, while <i>M. intracellulare</i> mainly affects immunocompetent hosts. This study aimed to elucidate the bacterial and host mechanisms underlying these differences.</p> Methods <p>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.</p> Results <p>K-mer GWAS identified lipid metabolism and transport genes (notably <i>mce</i>) enriched in isolates from hosts with different HIV statuses. Immunophenotyping showed that in HIV-negative patients, <i>M. intracellulare</i> infection elicited higher NKT cell frequencies than <i>M. avium</i>, a difference absent in HIV-positive hosts. In mice, anti-CD4<sup>−</sup>/<i>M. intracellulare</i> infection showed steadily increasing bacterial burden with time (ρ = 0.824), whereas <i>M. avium</i> exhibited no such trend. Early after infection (weeks 1–2), anti-CD4<sup>−</sup>/<i>M. avium</i> group had higher bacterial burden and NKT levels than anti-CD4<sup>−</sup>/<i>M. intracellulare</i>, but by week 4 the pattern reversed (all <i>p</i> &lt; 0.05). CD4 depletion eliminated species-specific differences in NKT activation, and at both weeks 2 (<i>p</i> &lt; 0.05) and 4 post-infection (<i>p</i> &gt; 0.05), the anti-CD4<sup>+</sup>/<i>M. avium</i> groups carried a higher bacterial burden than the anti-CD4<sup>+</sup>/<i>M. intracellulare</i> groups.</p> Conclusion <p>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 <i>M. avium</i> and <i>M. intracellulare</i> and highlights a potential target for host-directed interventions.</p>

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Deciphering the different Mycobacterium avium complex infections of HIV and non-HIV patients by bacterial GWAS and immune cells flow cytometry

  • 期刊论文

  • 发表日期：

    2026年2月12日

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  • Yue Hou,
  • Hong Sun,
  • Shuang Meng,
  • Wenzhao Xu,
  • Yanhua Yu,
  • Wenjing Wang,
  • Dingyi Liu,
  • Hongbing Jia,
  • Yajie Wang,
  • Hongqian Chu,
  • Zhaogang Sun

摘要

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.