Dihydrotestosterone enhances growth and infectivity of Leishmania Mexicana.

A strong sex-associated susceptibility towards Leishmania has been reported in males, yet little is known on the effect of hormones in Leishmania physiopathogenicity. Due to the enhanced susceptibility of males to Leishmania mexicana infections, we were interested in analysing the effect exerted by the main androgen produced in males (DHT) on L. mexicana promastigotes. Thus, the aim of this study was to assess the regulation exerted by dihydrotestosterone (DHT) on L. mexicana replication, infectivity, survival and development of tissue lesions. Experiments included growth curves of L. mexicana promastigotes incubated with different doses of DHT, their infection rate, intracellular survival and lesion development in BALB/c mice. Our data show that DHT significantly enhances parasite replication, infection rate and survival in bone marrow-derived macrophages (BMMФ). Promastigotes in the presence of DHT produced significantly larger lesions in BALB/c earlobes. These results suggest that DHT probably plays a critical role during L. mexicana infections, and the higher susceptibility of males possibly relates to benefits gained by the parasite from host-derived hormones. Our data shed new light on the physiopathology of Leishmania infections and are the first attempt to understand the direct interaction between Leishmania and androgens, particularly DHT. Understanding this trans-regulation process employed by parasites to exploit host molecules sheds new light on L. mexicana physiopathogenesis and opens a possible field for studies on drug development.

Effect of 1,25(OH)2D3 on BALB/c mice infected with Leishmania mexicana.

The most active metabolite of vitamin D, 1,25(OH)2D3 is a steroid hormone implicated in a wide range of cell functions such as differentiation, proliferation and apoptosis. Leishmania mexicana causes two kinds of cutaneous leishmaniasis: localized or diffuse. In this work we explored the effect of treatment of 1,25(OH)2D3 on a susceptible leishmaniasis mice model. A significant reduction in the lesion size was found in animals treated with 1,25(OH)2D3. Well preserved tissue and presence of large numbers of eosinophils and fibroblasts was found in the group treated with 1,25(OH)2D3. By contrast, destroyed epidermis was observed with large amount of neutrophils and epithelioid macrophages, on infected groups without 1,25(OH)2D3 treatment. The production of pro-inflammatory cytokines in mice infected and treated with 1,25(OH)2D3 was lower than the animals infected without 1,25(OH)2D3 treatment. Interestingly, there were no differences in the number of parasites in both groups. Finally, the amount of collagen was higher in animals with treatment compare with animals without 1,25(OH)2D3 treatment. In summary, mice treated with 1,25 (OH) 2D3 reflect a healing process without elimination of L. mexicana.

The efficacy of pentamidine combined with allopurinol and immunotherapy for the treatment of patients with diffuse cutaneous leishmaniasis.

A new treatment regimen was tested on patients with incurable diffuse cutaneous leshmaniasis (DCL) infected with Leishmania mexicana mexicana in Mexico. Two patients with advanced stages of the disease were treated with polychemotherapy (pentamidine and allopurinol) combined with recombinant human interferon-gamma (rIFN-gamma). For determination of the best medication, parasites isolated from patient lesions were exposed to available drugs both as promastigotes and as intracellular amastigotes. A synergistic effect was observed in vitro for the combination of pentamidine and allopurinol. Both patients were treated and recovered rapidly, but one of them developed insulin-dependent type I diabetes because of pentamidine toxicity. The complication was controlled and both patients were discharged with an apparent parasitologic cure, but after 3 months the two patients began to relapse. Our results suggest that allopurinol-pentamidine polychemotherapy, involving reduced dosage of pentamidine, combined with rIFN-gamma is an alternative for DCL patients infected with L. m. mexicana.

Treatment of two patients with diffuse cutaneous leishmaniasis caused by Leishmania mexicana modifies the immunohistological profile but not the disease outcome.

Two patients with diffuse cutaneous leishmaniasis caused by Leishmania mexicana were treated with two leishmanicidal drugs (pentamidine and allopurinol) combined with recombinant interferon-gamma restoring Th-1 favouring conditions in the patients. Parasites decreased dramatically in the lesions and macrophages diminished concomitantly, while IL-12-producing Langerhans cells and interferon-gamma- producing NK and CD8 + lymphocytes increased in a reciprocal manner. The CD4+/CD8 + ratio in the peripheral blood normalized. During exogenous administration of interferon-gamma the parasites' capacity to inhibit the oxidative burst of the patients' monocytes was abolished. Even though Th-1-favouring conditions were restored, both patients relapsed two months after therapy was discontinued. We conclude that the tendency to develop a disease-promoting Th-2 response in DCL patients is unaffected by, and independent of, parasite numbers. Even though intensive treatment in DCL patients induced Th-1 disease restricting conditions, the disease-promoting immunomodulation of few persistent Leishmania sufficed to revert the immune response.