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

Date Published: December 23, 2015

Publisher: Public Library of Science

Author(s): Elisangela Oliveira Freitas, Dirlei Nico, Marcus Vinícius Alves-Silva, Alexandre Morrot, Keith Clinch, Gary B. Evans, Peter C. Tyler, Vern L. Schramm, Clarisa B. Palatnik-de-Sousa, Michael P Pollastri.

Abstract: BackgroundImmucillins 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 FindingsBALB/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/SignificanceImmucillins 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.

Partial Text: Visceral leishmaniasis (VL) is a neglected tropical disease [1] caused by Leishmania (L.) donovani in India and Central Africa, by Leishmania (L.) infantum in the Middle East, Central Asia, China and Mediterranean and by Leishmania (L.) infantum chagasi in America. Approximately 0.2–0.4 million new human cases [2] are registered annually, 90% of them in India, Bangladesh, Brazil, Nepal, Sudan, South Sudan and Ethiopia [1]. The infection is an anthroponoses in India, Central Africa and China and a canid zoonosis in the Mediterranean, China and Americas.

Transition-state theory has led to the design of immucillins that inhibit the enzymatic activity of nucleoside hydrolases of parasitic protozoa [28, 35]. IA inhibits the NH of Chrithidia fasciculata, Trypanosoma brucei brucei, [24], L. (L.) major [35] and L. (L.) donovani [29], the purine nucleoside phosphorylase (PNP) of Trichomonas vaginalis [36] and the viral RNA polymerases of Marburg and Ebola filovirus [37]. Human PNP of erythrocytes and lymphocytes and human 5, methylthioadenosine phosphorylase have also been identified as targets of IA in humans [38]. Furthermore, IA also inhibits the replication of L (L.) infantum chagasi, L. (L.) amazonensis [29], and showed broad-spectrum antiviral activity against numerous viruses, including togavirus, bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses orthomyxovirus, Picornavirus and Flavivirus with untested targets [37]. IA has been shown to be safe in primates, and is now in phase 1 clinical trials for humans under the name BCX4430 [37].



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