Effector Mechanisms of Neutrophils within the Innate Immune System in Response to Mycobacterium tuberculosis Infection

Abstract

Neutrophils have a significant yet controversial role in the innate immune response to Mycobacterium tuberculosis (M. tb) infection, which is not yet fully understood. In addition to neutrophils’ well-known effector mechanisms, they may also help control infection of M. tb through the formation of neutrophil extracellular traps (NETs), which are thought to further promote the killing of M. tb by resident alveolar macrophages. Cytokines such as IFN-γ have now been shown to serve an immunomodulatory role in neutrophil functioning in conjunction to its pro-inflammatory function. Additionally, the unique transcriptional changes of neutrophils may be used to differentiate between infection with M. tb and other bacterial and chronic rheumatological diseases such as Systemic Lupus Erythematosus. Adversely, during the innate immune response to M. tb, inappropriate phagocytosis of spent neutrophils can result in nonspecific damage to host cells due to necrotic lysis. Furthermore, some individuals have been shown to be more genetically susceptible to tuberculosis (TB) due to a “Trojan Horse” phenomenon whereby neutrophils block the ability of resident macrophages to kill M. tb. Despite these aforementioned negative consequences, through the scope of this review we will provide evidence to support the idea that neutrophils, while sometimes damaging, can also be an important component in warding off M. tb infection. This is exemplified in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection or Type 2 diabetes mellitus. These individuals are at an increased risk of developing tuberculosis (TB) due to a diminished innate immune response associated with decreased levels of glutathione. Consequently, there has been a worldwide effort to limit and contain M. tb infection through the use of antibiotics and vaccinations. However, due to several significant limitations, the current bacille Calmette-Guerin vaccine (BCG, vaccine against TB) does not meet the criteria for universal utilization for all ages and populations across the globe. New research involving neutrophils has yielded a new vaccine called M. smegmatis-Ag85C-MPT51-HspX (mc2-CMX) that has been shown to elicit a humoral and cellular response against M. tb in mice that is superior to the BCG vaccine.

Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action

“…Although neutrophils have an effective antibacterial arsenal and also reside in granulomas, evidence suggests that their actions help bacteria transition from the latency stage to the active stage. For this reason, neutrophils are sometimes called “Trojan horses” in TB infection (Warren, Teskey, & Venketaraman, ). Mechanistically, neutrophils use MPO to generate ROS as their main antibacterial weapon.…”

Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response

“…Their main functions are phagocytosis and killing of invading bacteria through several mechanisms such as degranulation, production of reactive oxygen species (ROS) and formation of neutrophil extracellular traps (NETs) (72). The neutrophils secrete ROS, elastase, collagenase and myeloperoxidase, all of which can damage both the bacteria and the host cells (73). Their role during TB is complex and they can contribute to both defense and tissue damage (66).…”

“…ESAT-6 induced necrosis can also result in formation of neutrophil extracellular traps (NETs) with extruded DNA and granular proteins in a myeloperoxidase-dependent process (80,81). NETs function as a tool for host defense by trapping the pathogen and participating in the killing (73). Mtb-induced NETs can be phagocytosed by macrophages and activate a pro-inflammatory response (82).…”

Automatic Detection of Granuloma Necrosis in Pulmonary Tuberculosis Using a Two-Phase Algorithm: 2D-TB

“…Most human patients develop pulmonary TB, with disease restricted to the lungs following airborne infection with Mycobacterium tuberculosis. Infection incites complex host responses involving epithelial cells, dendritic cells, monocytes, macrophages, myeloid-derived suppressor cells, neutrophils, antigen-independent and antigen-specific lymphocytes, plasma cells, stem cells, stromal cells, and many effector molecules [2][3][4][5][6][7][8]. Cells recruited to the lungs form multiple lesion types, including diffuse lipid pneumonia, bronchiolar obstruction, and granulomas in humans and in experimental animal models [9][10][11][12][13][14][15][16][17].…”