Abstract
Certain individuals are able to resist Mycobacterium tuberculosis infection despite persistent and intense exposure. These persons do not exhibit adaptive immune priming as measured by tuberculin skin test (TST) and interferon-γ (IFN-γ) release assay (IGRA) responses, nor do they develop active tuberculosis (TB). Genetic investigation of individuals who are able to resist M. tuberculosis infection shows there are likely a combination of genetic variants that contribute to the phenotype. The contribution of the innate immune system and the exact cells involved in this phenotype remain incompletely elucidated. Neutrophils are prominent candidates for possible involvement as primers for microbial clearance. Significant variability is observed in neutrophil gene expression and DNA methylation. Furthermore, inter-individual variability is seen between the mycobactericidal capacities of donor neutrophils. Clearance of M. tuberculosis infection is favored by the mycobactericidal activity of neutrophils, apoptosis, effective clearance of cells by macrophages, and resolution of inflammation. In this review we will discuss the different mechanisms neutrophils utilize to clear M. tuberculosis infection. We discuss the duality between neutrophils' ability to clear infection and how increasing numbers of neutrophils contribute to active TB severity and mortality. Further investigation into the potential role of neutrophils in innate immune-mediated M. tuberculosis infection resistance is warranted since it may reveal clinically important activities for prevention as well as vaccine and treatment development.
Highlights
Not all individuals exposed to Mycobacterium tuberculosis become infected as inferred by a lack of T cell memory response to M. tuberculosis antigens
The association of uncontrolled neutrophil recruitment and pathology in TB would argue against a role of these cells in M. tuberculosis infection resistance
There is documented interindividual variability in the ability of neutrophils to kill M. tuberculosis suggesting that the role of neutrophils in an early encounter with M. tuberculosis may differ from the more integrated role in the presence of a strongly developed acquired immune response to the bacillus
Summary
Not all individuals exposed to Mycobacterium tuberculosis become infected as inferred by a lack of T cell memory response to M. tuberculosis antigens. Certain individuals who are highly exposed, never develop evidence of infection This suggests that they are naturally resistant to M. tuberculosis and can prevent infection via an innate immune response prior to adaptive immune cell priming, and are known as “innate resisters” [4]. In South African goldminers who have a documented high exposure to M. tuberculosis and an estimated LTBI prevalence of 89% in 2006, 13% of the HIV-negative participants had a TST = 0 mm response [15] Together, these studies suggest that 5–20% of the population may possess resistance to M. tuberculosis infection. In a highly TB endemic area in South Africa 20% of the highly exposed population remained TST negative which was stringently defined as TST = 0 mm This phenotype is linked to a major locus, TST1, which represents T cell-independent M. tuberculosis infection resistance [13]. Current genetic evidence suggests that the resistance phenotype is likely due to a combination of genetic variants synergistically contributing to the phenotype rather than a single genetic variant
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