Arbués Ainhoa, Schmidiger Sarah, Reinhard Miriam, Borrell Sonia, Gagneux Sebastien, Portevin Damien
Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
University of Basel, Basel, Switzerland.
Elife. 2025 Mar 31;13:RP99062. doi: 10.7554/eLife.99062.
The members of the complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets-a phenotype associated with dormancy-that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
导致人类结核病的结核分枝杆菌复合群（MTBC）成员包括10个系统发育谱系，它们在地理分布上存在差异。这种系统发育多样性对人类的影响仍知之甚少。在此，我们评估了代表五个主要MTBC谱系的14株临床菌株在宿主-病原体界面的表型特性。通过将人类肉芽肿模型与细菌载量评估、显微镜检查、流式细胞术和多重珠阵列相结合，我们观察到了相当大的谱系内多样性。然而，现代谱系总体上与生长速率增加和更明显的肉芽肿反应相关。MTBC谱系表现出积累甘油三酯脂滴的不同倾向——一种与休眠相关的表型——在谱系2中尤为明显，而在谱系3菌株中则有所减少。最有利的肉芽肿反应与强烈的CD4和CD8 T细胞活化以及由CXCL9、颗粒酶B和TNF介导的炎症反应相关。这两者在不同谱系的遗传距离较远的MTBC菌株中均与细菌增殖呈一致的负相关。综上所述，我们的数据表明，不同的毒力策略和保护性免疫特征与MTBC在谱系和菌株水平的遗传多样性相关。
