Extracellular adenosine triphosphate affects the response of human macrophages infected with Mycobacterium tuberculosis.

Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular adenosine triphosphate (ATP) indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into adenosine monophosphate (AMP), and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage but may also favor bacterial immune escape.

Hormonal contraception and HIV prevalence in four African countries.

BACKGROUND: The HIV seroprevalence among women aged 15-24 years was compared according to their pattern of contraceptive use in four African countries: Kenya, Lesotho, Malawi and Zimbabwe. STUDY DESIGN: Data were derived from Demographic and Health Surveys (DHS) conducted between 2003 and 2006 on representative samples, totaling 4549 women. RESULTS: It is indicated that users of depo-medroxyprogesterone acetate (DMPA) have a significantly higher seroprevalence than nonusers [odds ratio (OR)=1.82, 95% CI=1.63-2.03] and higher than users of oral contraceptives and users of traditional methods. The results were confirmed in a multivariate analysis including as controls, age, duration since first intercourse, urban residence, education, number of sexual partners in the last 12 months and marital status. A somewhat smaller net effect (OR=1.34, 95% CI=1.10-1.63) was found. In contrast, oral contraceptives and traditional methods did not show any risk for HIV (OR=0.96 and 0.92, respectively). CONCLUSION: The increased risk of DMPA was present in three of the four countries investigated, and significant in Zimbabwe and Lesotho, the countries with the highest HIV seroprevalence. The HIV risk attributable to DMPA remained small altogether and was estimated as 6% in the four countries combined.

Mycobacterium tuberculosis exploits the formation of new blood vessels for its dissemination.

The mechanisms by which the airborne pathogen Mycobacterium tuberculosis spreads within the lung and leaves its primary niche to colonize other organs, thus inducing extrapulmonary forms of tuberculosis (TB) in humans, remains poorly understood. Herein, we used a transcriptomic approach to investigate the host cell gene expression profile in M. tuberculosis-infected human macrophages (ΜΦ). We identified 33 genes, encoding proteins involved in angiogenesis, for which the expression was significantly modified during infection, and we show that the potent angiogenic factor VEGF is secreted by M. tuberculosis-infected ΜΦ, in an RD1-dependent manner. In vivo these factors promote the formation of blood vessels in murine models of the disease. Inhibiting angiogenesis, via VEGF inactivation, abolished mycobacterial spread from the infection site. In accordance with our in vitro and in vivo results, we show that the level of VEGF in TB patients is elevated and that endothelial progenitor cells are mobilized from the bone marrow. These results strongly strengthen the most recent data suggesting that mycobacteria take advantage of the formation of new blood vessels to disseminate.