Abstract
BackgroundNitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent. A previous study has demonstrated that 20% of the L. (V.) braziliensis isolated from initial cutaneous lesions of patients from the endemic area of Corte de Pedra, Bahia, Brazil, were NO resistant. Additionally, 5 to 11% of the patients did not respond to three or more antimony treatments" (refractory patients). The aim of this study is to investigate if there is an association between the resistance of L. (V.) braziliensis to NO and nonresponsiveness to antimony therapy and cytokine production.MethodsWe evaluated the in vitro toxicity of NO against the promastigotes stages of L. (V.) braziliensis isolated from responsive and refractory patients, and the infectivity of the amastigote forms of these isolates against human macrophages. The supernatants from Leishmania infected macrophage were used to measure TNF-α and IL-10 levels.ResultsUsing NaNO2 (pH 5.0) as the NO source, L. (V.) braziliensis isolated from refractory patients were more NO resistant (IC50 = 5.8 ± 4.8) than L. (V.) braziliensis isolated from responsive patients (IC50 = 2.0 ± 1.4). Four isolates were selected to infect human macrophages: NO-susceptible and NO-resistant L. (V.) braziliensis isolated from responsive and refractory patients. NO-resistant L. (V.) braziliensis isolated from refractory patients infected more macrophages stimulated with LPS and IFN-γ at 120 hours than NO-susceptible L. (V.) braziliensis isolated from refractory patients. Also, lower levels of TNF-α were detected in supernatants of macrophages infected with NO-resistant L. (V.) braziliensis as compared to macrophages infected with NO-susceptible L. (V.) braziliensis (p < 0.05 at 2, 24 and 120 hours), while no differences were detected in IL-10 levels.ConclusionThese data suggest that NO resistance could be related to the nonresponsiveness to antimony therapy seen in American Tegumentary Leishmaniasis.
Highlights
Nitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent
L. (V.) braziliensis isolated from refractory patients were more resistant to NO than L. (V.) braziliensis isolated from responsive patients We compared the resistance to NO against the responsiveness to antimony therapy of L. (V.) braziliensis isolates from patients
L. (V.) braziliensis isolated from antimony-refractory patients were more resistant to NO in vitro than L. (V.) braziliensis isolated from antimonyresponsive patients
Summary
Nitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent. (V.) braziliensis isolated from initial cutaneous lesions of patients from the endemic area of Corte de Pedra, Bahia, Brazil, were NO resistant. American Tegumentary Leishmaniasis (ATL) presents with a spectrum of nasopharynx It is most common in the areas of L. Promastigotes are transmitted to mammalian host by the bite of infected sand fly vector, which injects parasites into the host skin where they undergo facilitated phagocytosis by a macrophage and subsequently transform to obligate intracellular amastigotes [6,7]. IFN-g has been shown to act in synergy with another macrophage derived cytokine, tumor necrosis factor alpha (TNF-a), in activating macrophages and leading to the expression of inducible nitric oxide synthase (iNOS). (V.) braziliensis strains with resistance to NO there is an association between the size of the initial cutaneous lesion of ATL and NO susceptibility of the parasite isolate in vitro. Patients infected with NO-resistant L. braziliensis presented with larger cutaneous lesions than patients infected with NOsusceptible L. braziliensis [13]
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