Early infection accounts for approximately half of onward transmissions in this urban North American study. Therapy at early stages of disease may prevent onward HIV transmission.

Phagocyte functions are markedly inhibited after infection with the intracellular protozoan parasite Leishmania. This situation strongly favors the installation and propagation of this pathogen within its mammalian host. Previous findings by us and others have established that alteration of several signaling pathways (protein kinase C-, Ca 2؉ -and protein-tyrosine kinasesdependent signaling events) were directly responsible for Leishmania-induced macrophage (MØ) dysfunctions. Here we report that modulation of phosphotyrosine-dependent events with a protein tyrosine phosphatases (PTP) inhibitor, the peroxovanadium (pV) compound bpV(phen) (potassium bisperoxo(1,10-phenanthroline)oxovanadate(V i )), can control hostpathogen interactions by different mechanisms. We observed that the inhibition of parasite PTP resulted in an arrest of proliferation and death of the latter in coincidence with cyclin-dependent kinase (CDK1) tyrosine 15 phosphorylation. Moreover the treatment of MØ with bpV(phen) resulted in an increased sensitivity to interferon-␥ stimulation, which was reflected by enhanced nitric oxide (NO) production. This enhanced IFN-␥-induced NO generation was accompanied by a marked increase of inducible nitric oxide synthase (iNOS) mRNA gene and protein expression. Finally we have verified the in vivo potency of bpV(phen) over a 6-week period of daily administration of a sub-toxic dose. The results revealed its effectiveness in controlling the progression of visceral and cutaneous leishmaniasis. Therefore PTP inhibition of Leishmania and MØ by the pV compound bpV(phen) can differentially affect these eukaryotic cells. This strongly suggests that PTP plays an important role in the progression of Leishmania infection and pathogenesis. The apparent potency of pV compounds along with their relatively simple and versatile structure render them attractive pharmacological agents for the management of parasitic infections.

This study investigated whether Leishmania species, the etiologic agent of cutaneous (Leishmania major) and visceral (Leishmania donovani) leishmaniasis, could differentially elicit early inflammatory events in vivo correlating with the subsequent development of their reciprocal pathogenesis. By use of the murine air pouch system, injection of Leishmania led to a rapid and transient accumulation of a mixed population of leukocytes, and L. major recruited 31-fold more leukocytes than did controls, compared with 7-fold more leukocytes for L. donovani. L. major promastigotes were better than L. donovani promastigotes at inducing proinflammatory cytokine secretion and chemokine gene expression in pouch exudates. L. major infection elicited significantly increased chemokine receptor gene expression, compared with L. donovani infection. Collectively, the data reveal that L. major is a strong inducer of the early inflammatory response, compared with L. donovani, and suggest that such an immunologic event potentially could restrain this parasite to the inoculation site, favoring the development of local swelling and cutaneous lesions.

No abstract

Modulation of the phagocyte protein tyrosine phosphatase (PTP) SHP-1 by the parasite Leishmania favors its survival and propagation within its mammalian host. In vivo, the absence of SHP-1 leads to virtually absent footpad swelling, accompanied by enhanced inducible nitric oxide synthase expression. In this study, using an air pouch model, we show that viable motheaten SHP-1-deficient mice harbored a stronger inflammatory response against Leishmania infection than wild-type mice. This response was portrayed by higher pro-inflammatory cytokine (TNF-a, IL-1b and IL-6) expression and secretion and by greater chemokine and chemokine receptor expression. These inflammatory molecules were probably responsible for the stronger cellular recruitment, mainly of neutrophils, seen at the site of infection in viable motheaten mice within 6 h post inoculation. We also provide strong evidence that protein tyrosine phosphatases in general, and SHP-1 in particular, are important regulators of chemokine gene expression. Overall, this study suggests that the ability of Leishmania to induce SHP-1 activity in its host allows the taming of an otherwise strong innate inflammatory response that would be detrimental for its survival and progression.

The phosphotyrosine phosphatase inhibitor bpV(phen) has the ability to markedly decrease the progression of leishmaniasis in vivo. Here, we have identified the mechanisms that are responsible for this protective effect. We report that two potent peroxovanadium (pV) compounds, bpV(phen) and bpV(pic), control progression of leishmaniasis in a similar manner by modulating NO‐dependent microbicidal action. We observed that their injection can rapidly and transiently induce the expression of inducible NO synthase (iNOS) in livers of mice and enhance circulating nitrate levels. Treatment of mice with bpV(phen) or bpV(pic) completely controlled progression of leishmaniasis in an NO‐dependent manner, since inhibition of iNOS with aminoguanidine completely reversed this pV‐mediated protection. This NO‐dependent pV‐mediated protection was further demonstrated by the incapacity of bpV(phen)‐treated Nramp–/–, iNOS–/– mutant mice to control Leishmania major infection. Using an air pouch model, we showed that bpV(phen) can strongly modulate secretion of L. major‐induced pro‐inflammatory molecules and neutrophil recruitment. In addition, we observed that bpV(phen) per se can strongly induce the expression of Th1 type cytokines over Th2 in spleens of animals. Overall, this study has allowed us to establish the in vivo functional and immunological events involved in pV‐mediated protective mechanism against leishmaniasis and that NO plays a pivotal role in this process.

This study demonstrates that functionally active HLA-G polymorphisms are associated with altered risk of HIV-1 infection in African women. This provides evidence to support the hypothesis that modulation of HLA-G expression by HIV-1 can contribute to the risk of infection. Targeted interventions to reduce or block HLA-G expression in genital tissues could lead to novel strategies for the prevention of heterosexual HIV-1 transmission.

Prostaglandin E2 (PGE2) secretion during Leishmania infection has been reported. However, the signalling mechanisms mediating this response are not well understood. Since cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2) are involved in PGE2 synthesis in response to various stimuli, the implication of these enzymes was evaluated in Leishmania-infected phorbol myristate acetate-differentiated U937 human monocytic cell line. Time-course experiments showed that PGE2 synthesis increased significantly in parallel with COX-2 expression when cells were incubated in the presence of Leishmania donovani promastigotes or lipopolysaccharides (LPS). Increase in cPLA2 mRNA expression was only detected when cells were stimulated with LPS. Indomethacin, genistein, and H7, which are antagonists of COX-2, protein tyrosine kinase (PTK) and protein kinase C (PKC), respectively, inhibited PGE2 production induced by L. donovani and LPS. However, only H7 inhibited COX-2 mRNA synthesis, and there was a significant correlation between PGE2 inhibition and reduced COX-2 expression. Collectively, our results indicate that infection of U937 by L. donovani leads to the generation of PGE2 in part through a PKC-dependent signalling pathway involving COX-2 expression. They further reveal that PTK-dependent events are necessary for Leishmania-induced PGE2 generation, but not for COX-2 expression. A better understanding of the mechanisms by which Leishmania can induce PGE2 production could provide insight into the pathophysiology of leishmaniasis and may help to improve therapeutic approaches.