Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

Abstract

Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.

Analysis of immunological resistance to primary Mycobacterium tuberculosis infection in humans

“…Since we saw such a distinct B cell signature in the nonconverters, this suggests that other antibody-independent functions of B cells are driving the protection from infection and this is currently being assessed in our laboratory.In conclusion, despite being clinically healthy and showing no signs of latent infection by current tests, we were able to show differential immune responses in subjects who would later convert to a positive TST compared to those who remained TST negative. Our results support the recent proposed criteria to define resistance by Simmonds et al[8], including the use of both TST and QFT with multiple negative results in the first 12 months following exposure. The interesting B cell and Type I IFN signatures provide an avenue for analysis of mechanisms underlying the protection and could be targeted to enhance resistance to Mtb.…”

“…Several cell subsets have been proposed to control resistance to Mtb infection including macrophages, non-classical T cell subsets and B cells. Macrophage-dependent pathways that prevent bacterial uptake or rapidly clear Mtb before the development of an adaptive immune response define innate resisters while adaptive resisters are individuals in which T cell and B cell effector functions eliminate or restrict Mtb infections, either independently of IFN-γ production or through priming by non-protein antigens [8]. Further study is required to determine whether adaptive resisters have greater resistance to progression to active TB than individuals with traditionally defined LTBI [8].…”

“…Macrophage-dependent pathways that prevent bacterial uptake or rapidly clear Mtb before the development of an adaptive immune response define innate resisters while adaptive resisters are individuals in which T cell and B cell effector functions eliminate or restrict Mtb infections, either independently of IFN-γ production or through priming by non-protein antigens [8]. Further study is required to determine whether adaptive resisters have greater resistance to progression to active TB than individuals with traditionally defined LTBI [8]. Genome-wide association analysis has also identified loci that are associated with innate or adaptive resistance to Mtb infection [9].…”

Analysis of cellular and soluble profiles in QuantiFERON nonconverters, converters, and reverters in the Gambia

“…However, the mechanism underlying this is unclear . Analysis of individuals who appear to “resist” development of latent TB infection (LTBI) and those who can actively clear infection would provide novel insights into natural protective immunity to Mtb …”

“…5 Analysis of individuals who appear to "resist" development of latent TB infection (LTBI) and those who can actively clear infection would provide novel insights into natural protective immunity to Mtb. 6 Evidence for natural protection from Mtb infection comes from the consistent finding that a proportion of highly Mycobacterium tuberculosis (Mtb)-exposed individuals do not acquire Mtb infection. 7,8 This is best illustrated by the Lübeck disaster where~20% of infants vaccinated with Mtb-contaminated BCG did not get infected.…”