Abstract
BackgroundNitric oxide (NO•) plays a pivotal role as a leishmanicidal agent in mouse macrophages. NO• resistant Escherichia coli and Mycobacterium tuberculosis have been associated with a severe outcome of these diseases.MethodsIn this study we evaluated the in vitro toxicity of nitric oxide for the promastigote stages of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis parasites, and the infectivity of the amastigote stage for human macrophages. Parasites were isolated from patients with cutaneous, mucosal or disseminated leishmaniasis, and NO• resistance was correlated with clinical presentation.ResultsSeventeen isolates of L. (L.) amazonensis or L. (V.) braziliensis promastigotes were killed by up to 8 mM of more of NaNO2 (pH 5.0) and therefore were defined as nitric oxide-susceptible. In contrast, eleven isolates that survived exposure to 16 mM NaNO2 were defined as nitric oxide-resistant. Patients infected with nitric oxide-resistant Leishmania had significantly larger lesions than patients infected with nitric oxide-susceptible isolates. Furthermore, nitric oxide-resistant L. (L.) amazonensis and L. (V.) braziliensis multiplied significantly better in human macrophages than nitric oxide-susceptible isolates.ConclusionThese data suggest that nitric oxide-resistance of Leishmania isolates confers a survival benefit for the parasites inside the macrophage, and possibly exacerbates the clinical course of human leishmaniasis.
Highlights
Nitric oxide (NO) plays a pivotal role as a leishmanicidal agent in mouse macrophages
Evaluation of Leishmania spp. promastigotes resistance to NO and correlation with clinical disease The susceptibility of L. (L) amazonensis (n = 11) and L. (V) braziliensis (n = 17) promastigotes to NO toxicity was evaluated using two measures of parasite viability: first, the rate of [3H]-thymidine incorporation into parasite DNA, and second, a colorimetric measure of mitochondrial activity according to MTT metabolism to formazan
Our preliminary titrations led us to a definition of NO susceptibility as measured viability that is less than 5% of control parasites after exposure to 8 mM NaNO2
Summary
Nitric oxide (NO) plays a pivotal role as a leishmanicidal agent in mouse macrophages. NO resistant Escherichia coli and Mycobacterium tuberculosis have been associated with a severe outcome of these diseases. Leishmaniasis is a parasitic disease caused by the Leishmania spp. protozoa, transmitted to the skin of a mammalian host during the bite of an infected female sand fly vector. Infections range in severity from asymptomatic to disfiguring forms of tegumentary and potentially fatal visceral leishmaniasis [1,2]. American tegumentary leishmaniasis (ATL) presents a spectrum of clinical manifestations characterized by cutaneous (CL), mucosal (ML), disseminated (DL) and diffuse cutaneous leishmaniasis (DCL). Mucosal leishmaniasis (ML) is a destructive disease that predominantly affects the nasopharyngeal mucosa. The disease is most common in areas of L. (V.) braziliensis transmission and usually occurs months or years after cutaneous leishmaniasis [4]. DL is characterized by the appearance of multiple pleomorphic lesions in two or more noncontiguous areas of the body [5]
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