Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis

Citation: Freitas EO, Nico D, Alves-Silva MV, Morrot A, Clinch K, Evans GB, et al. (2015) Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis. PLoS Negl Trop Dis 9(12): e0004297. doi:10.1371/journal.pntd.0004297
Published: December 23, 2015

Abstract
Background: Immucillins ImmA (IA), ImmH (IH) and SerMe-ImmH (SMIH) are synthetic deazapurine nucleoside analogues that inhibit Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis multiplication in vitro without macrophage toxicity. Immucillins are compared to the Glucantime standard drug in the chemotherapy of Leishmania (L.) infantum chagasi infection in mice and hamsters. These agents are tested for toxicity and immune system response.
Methodology/Principal Findings: BALB/c mice were infected with 107 amastigotes, treated with IA, IH, SMIH or Glucantime (2.5mg/kg/day) and monitored for clinical variables, parasite load, antibody levels and splenocyte IFN-γ, TNF-α, and IL-10 expression. Cytokines and CD4+, CD8+ and CD19+ lymphocyte frequencies were assessed in uninfected controls and in response to immucillins. Urea, creatinine, GOT and GPT levels were monitored in sera. Anti-Leishmania-specific IgG1 antibodies (anti-NH36) increased in untreated animals. IgG2a response, high levels of IFN-γ, TNF-α and lower levels of IL-10 were detected in mice treated with the immucillins and Glucantime. Immucillins permitted normal weight gain, prevented hepato-splenomegaly and cleared the parasite infection (85–89%) without renal and hepatic toxicity. Immucillins promoted 35% lower secretion of IFN-γ in uninfected controls than in infected mice. IA and IH increased the CD4+ T and CD19+ B cell frequencies. SMIH increased only the proportion of CD-19 B cells. IA and IH also cured infected hamsters with lower toxicity than Glucantime.
Conclusions/Significance: Immucillins IA, IH and SMIH were effective in treating leishmaniasis in mice. In hamsters, IA and IH were also effective. The highest therapeutic efficacy was obtained with IA, possibly due to its induction of a TH1 immune response. Low immucillin doses were required and showed no toxicity. Our results disclose the potential use of IA and IH in the therapy of visceral leishmaniasis.
Author Summary: The IA, IH, and SMIH immucillins are known to impair the replication of promastigotes of L. (L.) infantum chagasi and L. (L.) amazonensis imucillins in vitro and impair the replication of intracellular amastigotes of L. (L.) infantum chagasi in vitro with no toxicity for macrophages. IA and IH also inhibit the enzymatic activity of Leishmania (L.) donovani nucleoside hydrolase (NH36) one of the purine salvage enzymes in these purine auxotrophs. In this work, we compared the efficacies of IA, IH and SMIH to the standard drug Glucantime in the therapy of L. (L.) infantum chagasi infection of mice and hamsters. IA and IH, at low concentrations, cured mice and hamsters from visceral leishmaniasis (VL). Unlike treatment with Glucantime, immucillin therapy showed no toxicity. We demonstrate that treatment of IA and IH also affects the induction of the immune system, a factor that might also contribute to VL therapy. This study shows significant promise in the development of safer drugs for leishmaniasis therapy.

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