Purinergic signaling and the p75 tumor necrosis factor-alpha receptor critically regulate mechanisms of resistance to M. tuberculosis
Intracellular pathogens, such as M. tuberculosis , have developed strategies for subverting microbicidal mechanisms and living within the host macrophage. However, a variety of signals, such as those mediated by the cytokines IFN-g and TNF-a, or by components of the mycobacterial cell wall, can activate macrophages to produce antimicrobial mediators, such as nitric oxide (NO). Conversely, as M. tuberculosis replicates within the macrophage, it can itself become toxic to the macrophage. The ultimate outcome of this relationship---destruction of bacilli by the macrophage, or successful parasitism of the macrophage by the bacillus---depends, in part, on the ability of the macrophage to become activated before lysis occurs. Thus, a better understanding of the signals and signal transduction pathways which control macrophage activation in response to infection will yield insights into the relationship between M. tuberculosis and its host.;One mechanism which may regulate macrophage activation and expression of microbicidal effector mechanisms is signaling by extracellular ATP through the P2 family of purinergic receptors. UV laser confocal analysis was used to examine alterations of Ca2+ signaling induced by infection of macrophages with BCG (a mycobacterial species related to M. tuberculosis ). The presence of purinergic receptors on the macrophage populations studied was characterized, and P2 receptor antagonists used to demonstrate that the Ca2+ response to BCG required concomitant signaling through P2 receptors. Inhibition of BCG-induced Ca2+ signaling by the ATP-degrading enzyme apyrase demonstrated dependence upon extracellular ATP. Together, these data demonstrate that BCG infection of macrophages is accompanied by rapid, short-term elevation of cytoplasmic Ca2+, and suggest an essential role for signaling by extracellular nucleotides and P2 purinergic receptors in the Ca2+ response to mycobacterial infection. Experiments were then performed to test the hypothesis that extracellular nucleotides and P2 receptors control macrophage NO and ROI production in response to bacterial infection.;The cytokine Tumor Necrosis Factor-a (TNF-a) and its receptors (TNFRs) play a crucial role in the host response to many intracellular pathogens, including M. tuberculosis. TNF-a acts through two receptors, of 55 and 75 KD molecular weight. Experiments with gene-disrupted mice have demonstrated that the p55 TNFR plays an essential role in mediating TNF-a-dependent anti-TB immunity. However, it is not yet clear whether the p55 receptor is sufficient, or whether it must synergize with the p75 TNFR to limit M. tuberculosis infection. (Abstract shortened by UMI.).
Source: Dissertation Abstracts International, Volume: 61-09, Section: B, page: 4644.;Advisors: Barry R. Bloom.