Immunology ofMycobacterium tuberculosisInfections

Abstract

Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB), remains a significant global public health burden (1). In 2016, there were 10.4 million new TB cases reported globally and nearly 1.7 million TB-related deaths (1). Understanding the host response to M. tuberculosis infection is a key aspect of efforts to eradicate TB through the development of effective vaccines and immune therapeutics. M. tuberculosis is an intracellular pathogen transmitted via inhalation of aerosolized, bacteria-containing droplets. Innate immune cells in the lungs, primarily macrophages, dendritic cells, monocytes, and neutrophils, readily phagocytose M. tuberculosis and are the earliest defenders against the pathogen. The transformation of bacteria-containing phagosomes into acidified, antimicrobial compartments is a central tenet of defense against M. tuberculosis. In this regard, the production of interferon-γ (IFN-γ), which can activate infected myeloid cells and inhibit bacterial replication, is a well-known antimycobacterial contribution by adaptive immune cells such as CD4 and CD8 T cells. Despite pressures from host immunity, M. tuberculosis is able to persist in the host. M. tuberculosis infection results in hallmark lesions called granulomas, which are initially aggregates of infected and uninfected myeloid cells circumscribed by a lymphocytic cuff. The granuloma is thought to prevent bacterial dissemination to extrapulmonary sites but can also become a niche for long-term bacterial persistence. M. tuberculosis has evolved myriad strategies to evade and subvert immune responses to persist within a host, and it is becoming increasingly clear that the immune response to M. tuberculosis infection involves contributions from a wide variety of innate and adaptive immune cells. A clearer understanding of the complex cross talk between M. tuberculosis and host immunity is essential for the development of efficacious TB vaccines. Despite being developed nearly a century ago, Mycobacterium bovis bacillus Calmette-Guérin (BCG), an attenuated strain of M. bovis, remains the only licensed vaccine against TB. Vaccination with BCG provides protection against severe forms of disseminated TB in children but has variable efficacy in preventing pulmonary disease in children and adults (2 – 4). However, the immunological basis for the poor efficacy of BCG remains unclear. Moreover, long-held concepts regarding the nature of desired immune responses in an ideal TB vaccine, namely, the induction of antigen-specific CD4 T cells producing IFN-γ, are being updated to reflect the expanding knowledge of host immunity to M. tuberculosis infection gathered from animal models and human cohort studies. Advances in imaging and single-cell technologies combined with high-throughput approaches and systems-based analyses are providing more information on the immune response to M. tuberculosis infection at increasingly higher resolutions. As our understanding of the host response to M. tuberculosis infection grows, opportunities to leverage knowledge of the immunology of M. tuberculosis infection toward improving therapeutics and vaccines for TB are increasing.