Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.

Abstract

Sllmmal~Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon % and lipopolysaccharide or tumor necrosis factor or, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line Dg, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymaticaUy generated H202, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the t-arginine-dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the micobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the r-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs

“…1 and 3) and that B lymphocytes from murine tuberculous lungs express CXCR5 and migrate toward CXCL13 (26). In addition, the expression of NOS2 and Toll-like receptor 2 (TLR2) (the former is expressed in immunologically activated macrophages [8,25,36] and the latter is a molecule that plays an important role in signaling the interaction of M. tuberculosis components with host cells [23,28,37,41]) was evaluated.…”

The innate immune response in human tuberculosis

“…reactive oxygen and nitrogen species (ROS and RNS) as well as toxic metals. In the murine model of Mtb infection, the importance of nitric oxide (NO) and RNS for the control of intracellular mycobacterial replication and disease is well established (Chan et al ., 1992). In human macrophages, however, the role of NO is less clear.…”

The C‐terminal of CysM from Mycobacterium tuberculosis protects the aminoacrylate intermediate and is involved in sulfur donor selectivity

“…These compounds are used by phagocytic cells to eliminate internalized bacteria [3,4], but several pathogens, for instance Salmonella typhimurium and M. tuberculosis, are able to escape elimination which leads to long term survival and persistent infection [5].…”