Erika J Hughes, Charlie J Pyle, Mark Chambers, Jana Travnickova, Thabo Mpotje, Jacob P Lowy, Nathan T Strang, Carson E Carranza, Henry K E Ohman, Threnesan Naidoo, Liuyang Wang, Dennis C Ko, Jadee L Neff, Simon G Gregory, Clare M Smith, Jason E Stout, Fred B Lih, Matthew L Edin, Darryl C Zeldin, E Elizabeth Patton, Mohlopheni J Marakalala, Alasdair Leslie, David M Tobin
Genetic variation at the leukotriene A4 hydrolase (LTA4H) locus is associated with tuberculosis (TB) severity and outcome. Here, we define a unique population of peripheral fibroblasts at the mycobacterial granuloma, the central immune structure in TB, whose recruitment and functions are coordinated by lta4h-dependent signals. Using single-cell profiling of zebrafish mycobacterial infections, we identify a layer of lta4h-dependent recruited fibroblasts at the granuloma's edge with mesenchymal and stem-like expression signatures, including aldh1a3 expression. Ablation of these cells compromises bacterial containment at the structure's periphery. Similarly, genetic disruption of apolipoprotein D, produced specifically in granuloma-associated fibroblasts, results in an altered eicosanoid balance, decreased inflammation, and increased dissemination of infection. In humans, this granuloma-associated fibroblast population is distinct from myofibroblasts, interacts with LTA4H-expressing macrophages, and is prominent across diverse TB granuloma types. These results link a host genetic susceptibility locus to the recruitment and function of a specialized fibroblast population that limits bacterial dissemination.