Genetic Resistance to Mycobacterium tuberculosis Infection and Disease

Abstract

Natural history studies of tuberculosis (TB) have revealed a spectrum of clinical outcomes after exposure to Mycobacterium tuberculosis, the cause of TB. Not all individuals exposed to the bacterium will become diseased and depending on the infection pressure, many will remain infection-free. Intriguingly, complete resistance to infection is observed in some individuals (termed resisters) after intense, continuing M. tuberculosis exposure. After successful infection, the majority of individuals will develop latent TB infection (LTBI). This infection state is currently (and perhaps imperfectly) defined by the presence of a positive tuberculin skin test (TST) and/or interferon gamma release assay (IGRA), but no detectable clinical disease symptoms. The majority of healthy individuals with LTBI are resistant to clinical TB, indicating that infection is remarkably well-contained in these non-progressors. The remaining 5-15% of LTBI positive individuals will progress to active TB. Epidemiological investigations have indicated that the host genetic component contributes to these infection and disease phenotypes, influencing both susceptibility and resistance. Elucidating these genetic correlates is therefore a priority as it may translate to new interventions to prevent, diagnose or treat TB. The most successful approaches in resistance/susceptibility investigation have focused on specific infection and disease phenotypes and the resister phenotype may hold the key to the discovery of actionable genetic variants in TB infection and disease. This review will not only discuss lessons from epidemiological studies, but will also focus on the contribution of epidemiology and functional genetics to human genetic resistance to M. tuberculosis infection and disease.

Keywords: host genetics; resistance; resisters; susceptibility; tuberculosis.

Figure 1

A simplified representation of the Mycobacterium tuberculosis infection spectrum and outcomes. The bacteria enter the respiratory system of the host via inhaled droplets and are engulfed by macrophages and dendritic cells. There are four potential outcomes after bacterial inhalation: (i) M. tuberculosis is immediately eliminated by the pulmonary immune system, (ii) the bacteria are contained in granulomas by recruited adaptive immune cells (including T cells and B cells) and infection does not progress to active TB. Although this containment can last for a lifetime, M. tuberculosis can also disseminate from granulomas (reactivation) or reinfection with another mycobacterial strain can occur, resulting in active TB, (iii) sub-clinical disease characterized by intermittent symptoms and periodic infectiousness, or (iv) infection develops into active TB. Adapted from Pai et al. (3) and Möller et al. (4).