RT Journal Article
SR Electronic
T1 Soluble immune mediators orchestrate protective <em>in vitro</em> granulomatous responses across <em>Mycobacterium tuberculosis</em> complex lineages
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.05.21.595219
DO 10.1101/2024.05.21.595219
A1 Arbués, Ainhoa
A1 Schmidiger, Sarah
A1 Reinhard, Miriam
A1 Borrell, Sònia
A1 Gagneux, Sébastien
A1 Portevin, Damien
YR 2025
UL http://biorxiv.org/content/early/2025/02/04/2024.05.21.595219.abstract
AB The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise ten 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 in vitro 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.Competing Interest StatementThe authors have declared no competing interest.