Human Macrophage Responses to Clinical Isolates from the Mycobacterium tuberculosis Complex Discriminate between Ancient and Modern Lineages

Abstract

The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC). Measurement of cytokines from infected human peripheral blood monocyte-derived macrophages revealed a wide variation in the response to different strains. The same pattern of high or low response to individual strains was observed for different pro-inflammatory cytokines and chemokines, and was conserved across multiple human donors. Although each major phylogenetic lineage of MTBC included strains inducing a range of cytokine responses, we found that overall inflammatory phenotypes differed significantly across lineages. In particular, comparison of evolutionarily modern lineages demonstrated a significant skewing towards lower early inflammatory response. The differential response to ancient and modern lineages observed using GM-CSF derived macrophages was also observed in autologous monocyte-derived dendritic cells and murine bone marrow-derived macrophages, but not in human unfractionated peripheral blood mononuclear cells. We hypothesize that the reduced immune responses to modern lineages contribute to more rapid disease progression and transmission, which might be a selective advantage in the context of expanding human populations. In addition to the lineage effects, the large strain-to-strain variation in innate immune responses elicited by MTBC will need to be considered in tuberculosis vaccine development.

Author Summary

Mycobacterium tuberculosis is a long-standing human pathogen spread by aerosol transmission between individuals interacting in close social groups. It can be anticipated that the evolution of M. tuberculosis will parallel the evolution of human societies, and the phylogeny as determined by whole genome sequencing of clinical isolates is indeed consistent with emergence of the pathogen with modern humans in Africa and its subsequent dissemination along routes of human migration and trade. The present study was designed to test the hypothesis that the genetic diversity of M. tuberculosis isolates would be reflected in a corresponding diversity in their biological properties. In particular, we explored the interaction of different isolates with the innate immune system, which plays important contrasting roles in initial resistance to infection and in disease transmission. We observed a difference in the innate immune response when we compared isolates belonging to “modern” lineages that have evolved amongst high-density populations in regions of recent massive demographic expansion, with isolates belonging to “ancient” lineages selected in older low-density human populations. Our results provide insights into host-pathogen co-evolution and into fundamental mechanisms underlying the pathogenesis of M. tuberculosis.