Deep CyTOF immune profiles of ex vivo granulomatous responses to Mycobacterium tuberculosis differ with European and African geographical origin

Genetic and environmental factors influence human immunity and modulate responses to infection. Accounting for immune heterogeneity across human populations is critical to the design of novel vaccines and host-directed interventions that would optimally benefit populations experiencing the highest disease burden. Tuberculosis (TB) burden is unevenly distributed across geographical regions and our understanding of the differential immune response to Mycobacterium tuberculosis (Mtb) across human populations remains limited. Here, we sought to evaluate the impact of geographical origin on ex vivo granulomatous responses to Mtbinfection. We found that peripheral blood mononuclear cells (PBMCs) from healthy African donors exhibited greater control of Mtbgrowth ex vivo than those isolated from European individuals. High-dimensional single-cell profiling of the granulomatous responses by cytometry by time-of-flight (CyTOF) revealed divergent profiles based on the specimens' geographical origin. Monocytes from European donors displayed a pro-inflammatory phenotype - correlating with Mtbgrowth -, whereas PBMCs of African individuals were enriched in activated, cytotoxic T cells - correlating with Mtbcontrol. Reduced inflammatory response in African monocytes following various microbial stimulations was confirmed. Taken together, our comprehensive immune profiling indicates that environmental and genetic factors shape a cytotoxic-regulatory response that promotes bacterial control. Against the current "one-treatment-fits-all" approach, our findings support the use of specimens from intervention-relevant settings to inform the targeted design of TB vaccines and host-directed interventions.