Antibodies as key mediators of protection against Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is caused by infection with the bacterial pathogen Mycobacterium tuberculosis (M.tb) in the respiratory tract. There was an estimated 10.6 million people newly diagnosed with TB, and there were approximately 1.3 million deaths caused by TB in 2022. Although the global prevalence of TB has remained high for decades and is an annual leading cause of death attributed to infectious diseases, only one vaccine, Bacillus Calmette-Guérin (BCG), has been approved so far to prevent/attenuate TB disease. Correlates of protection or immunological mechanisms that are needed to control M.tb remain unknown. The protective role of antibodies after BCG vaccination has also remained largely unclear; however, recent studies have provided evidence for their involvement in protection against disease, as biomarkers for the state of infection, and as potential predictors of outcomes. Interestingly, the antibodies generated post-vaccination with BCG are linked to the activation of innate immune cascades, providing further evidence that antibody effector functions are critical for protection against respiratory pathogens such as M.tb. In this review, we aim to provide current knowledge of antibody application in TB diagnosis, prevention, and treatment. Particularly, this review will focus on 1) The role of antibodies in preventing M.tb infections through preventing Mtb adherence to epithelium, antibody-mediated phagocytosis, and antibody-mediated cellular cytotoxicity; 2) The M.tb-directed antibody response generated after vaccination and how humoral profiles with different glycosylation patterns of these antibodies are linked with protection against the disease state; and 3) How antibody-mediated immunity against M.tb can be further explored as early diagnosis biomarkers and different detection methods to combat the global M.tb burden. Broadening the paradigm of differentiated antibody profiling and antibody-based detection during TB disease progression offers new directions for diagnosis, treatment, and preventative strategies. This approach involves linking the aforementioned humoral responses with the disease state, progression, and clearance.

Keywords: LTBI (latent TB infection); active tuberculosis (ATB); antibody; biomarkers; serology; systems immunology; tuberculosis.

Figure 1

Protective roles for antibodies in M.tb control. (A) Antibodies consist of a Fab region which directly binds to target antigens and an Fc region which binds to cell-surfaced expressed receptors. The antibodies can bind to the surface of antigens and mediate different immunity functions. (B) Antibodies can leverage both their Fab and Fc domains to protect against M.tb. This can be done through direct binding of the bacteria to prevent adherence to the epithelium, opsinophagocytosis, cellular cytotoxicity activation, and complement deposition. (C) The M.tb not bound by the antibodies are able to replicate in the macrophages and inhibit the formation of phagolysosome. (D) while the antibody recognition helps the macrophage to lysis the M.tb via lysosome. (E) The monocytes also can be differentiated by the anti-PPE36 and anti-ESAT-6 antibodies into M1-polarized macrophages which release inflammatory cytokines to inhibit the self-replication of M.tb in the infected macrophage.

Figure 2

Translating antibody-based readouts novel vaccine platforms. Composite profiling of the total humoral profile can be investigated in the future with differentiated glycosylation signatures in favor of future vaccine designs against TB.

Figure 3

Translating antibody-based readouts to biomarkers of disease states. Antibodies specific to M.tb targets can be analyzed at the isotype and subclass level. Additionally, post-translational modifications can be identified on antigen-specific antibodies to identify signatures of disease states such as latency and active TB.