Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion?

Abstract

Adult or postprimary tuberculosis (TB) accounts for most TB cases. Its hallmark is pulmonary cavitation, which occurs as a result of necrosis in the lung in individuals with tuberculous pneumonia. Postprimary TB has previously been known to be associated with vascular thrombosis and delayed-type hypersensitivity, but their roles in pulmonary cavitation are unclear. A necrosis-associated extracellular cluster (NEC) refers to a cluster of drug-tolerant Mycobacterium tuberculosis attached to lysed host materials and is proposed to contribute to granulomatous TB. Here we suggest that NECs, perhaps due to big size, produce a distinct host response leading to postprimary TB. We propose that vascular thrombosis and pneumonia arise from NEC and that these processes are promoted by inflammatory cytokines produced from cell-mediated delayed-type hypersensitivity, such as interleukin-17 and gamma interferon, eventually triggering necrosis in the lung and causing cavitation. According to this view, targeting NEC represents a necessary strategy to control adult TB.

Strategies to Improve Vaccine Efficacy against Tuberculosis by Targeting Innate Immunity

“…In contrast to virulent M. tuberculosis , BCG induces apoptosis in macrophages, especially upon IFNγ activation ( 31 ). These findings are corroborated by us as well as others showing that attenuated M. tuberculosis strains as well as BCG primarily induce apoptosis in neutrophils, whereas virulent M. tuberculosis strains induce necrotic cell death in both, macrophages and neutrophils ( 11 , 32 – 34 ). Moreover, apoptosis has been described as a defense mechanism against M. tuberculosis ( 35 ).…”

Mycobacterium tuberculosis replicates within necrotic human macrophages

“…Although in vitro and in vivo studies highlight the importance of host cell death modes during mycobacterial control or dissemination, the mode of host cell death in the pathogenesis of human tuberculosis is not completely understood. In tuberculosis, apoptosis is generally considered to be a part of a host protective response, whereas necrosis is considered to be a pathway for bacterial dissemination and granuloma cavity formation ( Behar et al, 2010 ; Ramakrishnan, 2012 ; Wong and Jacobs, 2016 ). Apoptosis is believed to help with the eradication of M. tuberculosis ( Keane et al, 2000 ; Behar et al, 2010 ), and, unsurprisingly, this pathogen has strategies to inhibit apoptosis ( Velmurugan et al, 2007 ).…”

Manipulation of Host Cell Organelles by Intracellular Pathogens

“…Granuloma formation is the hallmark of TB pathogenesis and can be defined as an accumulation of various immune cells including differentiated and infected macrophages that create the inner core, as well as surrounding T- and B-lymphocytes ( Figure 7 ) [ 152 ]. Granulomas can lead to severe tissue damage due to macrophages undergoing MTB-induced necrosis that might promote bacterial replication as necrosis liberates components utilized by MTB [ 153 , 154 ]. Although granulomas are temporally restricting bacterial spread, they also support MTB as protective niche [ 155 ].…”