The Phagocyte Oxidase Controls Tolerance to Mycobacterium tuberculosis Infection

Abstract

Protection from infectious disease relies on two distinct strategies: antimicrobial resistance directly inhibits pathogen growth, whereas infection tolerance protects from the negative impact of infection on host health. A single immune mediator can differentially contribute to these strategies in distinct contexts, confounding our understanding of protection to different pathogens. For example, the NADPH-dependent phagocyte oxidase (Phox) complex produces antimicrobial superoxide and protects from tuberculosis (TB) in humans. However, Phox-deficient mice display no sustained resistance defects to , suggesting a more complicated role for NADPH Phox complex than strictly controlling bacterial growth. We examined the mechanisms by which Phox contributes to protection from TB and found that mice lacking the Cybb subunit of Phox suffered from a specific defect in tolerance, which was caused by unregulated Caspase-1 activation, IL-1β production, and neutrophil influx into the lung. These studies imply that a defect in tolerance alone is sufficient to compromise immunity to and highlight a central role for Phox and Caspase-1 in regulating TB disease progression.

Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of Mycobacterium tuberculosis

“…Alternatively, the NADPH oxidase might generate phagosomal membrane damage, which is known to promote pathogen ubiquitination, adaptor recruitment, and xenophagy (53,54). We observed NADPH oxidase recruitment in TMZ-treated Atg5 cKO macrophages, yet TMZ failed to restrict growth of Mtb in the absence of xenophagy, arguing against direct antimycobacterial activity of the NADPH oxidase, consistent with other recent studies (40,55). We conclude that the antimycobacterial activity of ROS is primarily based upon its ability to activate lysosomal trafficking pathways or depends upon a combination of lysosomal trafficking and ROS.…”

Mycobacterium tuberculosisevasion of Guanylate Binding Protein-mediated host defense in mice requires the ESX1 secretion system

“…To date, the type III secretion system effector protein IpaH9.8 from Shigella flexneri is the only other described GBP antagonist (36)(37)(38)(39). In the cytosol of mammalian cells, where S. flexneri replicates, IpaH9.8 targets GBP1 for degradation thereby interfering with direct GBP binding to the Shigella outer membrane, a process by which GBP1 disrupts the function of a membrane-bound Shigella virulence factors required for actin-based motility and bacterial dissemination (36)(37)(38)40) however, these mechanisms appear to play a small role in directly controlling Mtb growth in vivo (32,33,41). Instead, these mediators are required to inhibit persistent inflammation and to prevent disease progression.…”

“…To generate bone marrow derived macrophages (BMDMs), marrow was isolated from femurs and tibia of age and sex matched mice as previously described (33). Cells were then incubated in DMEM (Sigma) containing 10% fetal bovine serum (FBS) and 20% L929 supernatant.…”

Tolerating the Unwelcome Guest; How the Host Withstands Persistent Mycobacterium tuberculosis

“…In other disease contexts Phox deficiencies have been found cause inflammatory disease, particularly those related to IL-1β activation ( 54 ). Recent work shows that Phox is also critical for tolerance to Mtb infection (Figure 1 ) ( 55 ). Phox-deficient mice have no deficiency in bacterial control, yet Phox-deficient animals accumulate high numbers of neutrophils in an IL-1β dependent fashion, leading to exacerbated disease ( 55 ).…”

“…Recent work shows that Phox is also critical for tolerance to Mtb infection (Figure 1 ) ( 55 ). Phox-deficient mice have no deficiency in bacterial control, yet Phox-deficient animals accumulate high numbers of neutrophils in an IL-1β dependent fashion, leading to exacerbated disease ( 55 ). Similar to the role of Nos2, the ROS produced by Phox control tolerance by inhibiting the activation of the NLRP3 inflammasome which reduces IL-1β production and limits neutrophil influx to the infected lung.…”