Neutrophils: Innate Effectors of TB Resistance?

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.

Keywords: Mycobacterium; NETs; antimicrobial; inflammation; necrosis; protection; tuberculosis.

Figure 1

(A) Alveolar macrophages (AM) are the first cells to encounter M. tuberculosis after inhalation of the bacillus. Acute pro-inflammatory signals are released by AM and local tissue macrophages to recruit neutrophils to the site of infection.(B) Neutrophils use a variety of mechanisms to mediate M. tuberculosis infection. These included phagocytosis, degranulation, ROS formation and NET release. NETs transfer Hsp72 to adjacent macrophages inducing a pro-inflammatory response.(C) Interaction of recruited neutrophils with M. tuberculosis mediates the activation of several pathways which contribute to inflammation and clearance of M. tuberculosis infection. Interleukin-1β (IL-1β) release is mostly mediated in an inflammasome dependent manner. Tumour necrosis factor (TNF) induces NF-κB which mediates the induction of gene expression of IL-1β in neutrophils. Interferon-γ (IFN-γ) may also regulate the release of IL-1β. IL-1β is a key player in mediating the release of prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) both of which contribute to inflammation and the recruitment of neutrophils. (D) PGE₂ eventually becomes a stop signal and has a negative feedback on cyclo-oxygenase-2 (COX-2) and 5-lipoxygenase (5-LO). The production of lipoxin A4 (LXA4) is favoured. In addition, AnnexinA1 (ANX1) stimulates IL-10 release by macrophages. Neutrophils express inducible nitric oxide synthase (iNOS) which has a further negative feedback on IL-1β release. The net effect is an increase in neutrophil apoptosis and clearance by tissue macrophages. More macrophages are recruited and further neutrophil recruitment is inhibited and inflammation is resolved.