Shaping the niche in macrophages: Genetic diversity of the M. tuberculosis complex and its consequences for the infected host.

Pathogenic mycobacteria of the Mycobacterium tuberculosis complex (MTBC) have co-evolved with their individual hosts and are able to transform the hostile environment of the macrophage into a permissive cellular habitat. The impact of MTBC genetic variability has long been considered largely unimportant in TB pathogenesis. Members of the MTBC can now be distinguished into three major phylogenetic groups consisting of 7 phylogenetic lineages and more than 30 so called sub-lineages/subgroups. MTBC genetic diversity indeed influences the transmissibility and virulence of clinical MTBC isolates as well as the immune response and the clinical outcome. Here we review the genetic diversity and epidemiology of MTBC strains and describe the current knowledge about the host immune response to infection with MTBC clinical isolates using human and murine experimental model systems in vivo and in vitro. We discuss the role of innate cytokines in detail and portray two in our group recently developed approaches to characterize the intracellular niches of MTBC strains. Characterizing the niches and deciphering the strategies of MTBC strains to transform an antibacterial effector cell into a permissive cellular habitat offers the opportunity to identify strain- and lineage-specific key factors which may represent targets for novel antimicrobial or host directed therapies for tuberculosis.