Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?

Abstract

Despite the discovery of the tuberculosis (TB) bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis (MTb). Understanding the genetic and immunologic factors that influence human susceptibility could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease. Although a series of studies over the past 50 years suggests that host genetics influences resistance to TB, a comprehensive understanding of which genes and variants are associated with susceptibility is only partially understood. In this article, we review recent advances in our understanding of human variation of the immune system and its effects on macrophage function and influence on MTb susceptibility. We emphasize recent discoveries in human genetic studies and correlate these findings with efforts to understand how these variants alter the molecular and cellular functions that regulate the macrophage response to MTb.

Fig. 1. Macrophage response to MTb

Depicted are the molecules that have been identified as important mediators of the macrophage response to MTb. iNOS, inducible nitric oxide synthase; LRR, leucine-rich region. MTb is recognized by several receptors and ingested by the alveolar macrophage. For example, MTb expresses several ligands that activate TLRs, in turn leading to signaling downstream of the MyD88 adapter protein. See text for more detail.

Fig. 2. Cellular immune response to MTb

After infection, activated macrophages secrete cytokines and chemokines that activate macrophages, T cells, neutrophils, or NK cells. T cells and NK cells produce IFN-γ that acts with other cytokines to activate macrophages to produce NO, which contributes to clearance of MTb. See text for more detail.