sphingosine-1-phosphate and Tuberculosis--Pulmonary

Lysophospholipids may play an important protective role during primary infection of Mycobacterium tuberculosis (MTB) by enhancing innate antimycobacterial immune response of both macrophages and alveolar epithelial cells. Here, we show that treatment with lysophosphatidic acid (LPA) of mice aerogenically infected with MTB immediately after infection results in a significant early reduction of pulmonary CFUs and of histopathological damage in comparison with control mice. In contrast, treatment of acute disease does not result in any improvement of both microbiological and histopathological parameters. Altogether, these results show that LPA treatment can exert protective effect if administrated during primary infection, only.

Topics: Acute Disease; Animals; Colony Count, Microbial; Female; Lung; Lysophospholipids; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Sphingosine; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Sphingosine 1-phosphate (S1P) has recently been reported to induce antimycobacterial activity in vitro and in a mouse model of in vivo Mycobacterium tuberculosis infection. However, its role in the course of pulmonary tuberculosis in humans is still not known. This study shows that S1P levels in airway surface fluid of tuberculosis (TB) patients are significantly less than those observed in non-TB control patients. Moreover, the in vitro stimulation of bronchoalveolar lavage cells coming from TB patients with S1P significantly reduces intracellular growth of endogenous mycobacterial isolates. These results show that, in the course of pulmonary TB, airway epithelial fluid-associated S1P may play a protective role in the containment of intracellular mycobacterial growth and that its decrease may represent a novel pathogenic mechanism through which M. tuberculosis favors its replication.

Topics: Adult; Animals; Cells, Cultured; Cricetinae; Female; Humans; Lysophospholipids; Male; Middle Aged; Mycobacterium tuberculosis; Sphingosine; Tuberculosis, Pulmonary

Sphingosine 1-phosphate (S1P), a polar sphingolipid metabolite, is involved in a wide spectrum of biological processes, including Ca(++) mobilization, cell growth, differentiation, motility, and cytoskeleton organization. Here, we show a novel role of S1P in the induction of antimicrobial activity in human macrophages that leads to the intracellular killing of nonpathogenic Mycobacterium smegmatis and pathogenic M. tuberculosis. Such activity is mediated by host phospholipase D, which favors the acidification of mycobacteria-containing phagosomes. Moreover, when it was intravenously injected in mycobacteria-infected mice, S1P reduced mycobacterial growth and pulmonary tissue damage. These results identify S1P as a novel regulator of the host antimicrobial effector pathways.

Topics: Animals; Blotting, Western; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Histocytochemistry; Humans; Lung; Lysophospholipids; Macrophages, Alveolar; Mice; Microscopy, Confocal; Mycobacterium smegmatis; Mycobacterium tuberculosis; Phospholipase D; Sphingosine; Spleen; Statistics, Nonparametric; Tuberculosis, Pulmonary