| Summary: | Dogs are the main reservoir for <i>Leishmania infantum,</i> manifesting from a subclinical to a fatal disease. Limited treatments are available, although new antiparasitics and immunomodulators are pursued. Polyhexamethylene biguanide (PHMB) has a broad antimicrobial spectrum, including antiparasitic activity. Here, we evaluated the potential for Toll-like receptor agonists (TLRa) and PHMB alone, and as polyplex nanoparticles containing PHMB and TLR4 or TLR9 agonists, to selectively kill <i>L. infantum</i>. Susceptibility of <i>L. infantum</i> promastigotes to PHMB, miltefosine, and allopurinol was performed, and the half-maximum inhibitory concentrations (IC<sub>50</sub>) were determined. Then, DH-82 cells were infected and treated with PHMB alone or combined with TLR4a (MPLA-SM) or TLR9a (CpG ODNs) and allopurinol alone. The IC<sub>50</sub> values of <i>L. infantum</i> promastigotes were PHMB (1.495 µM), miltefosine (9.455 µM), and allopurinol (0.124 µM). After infection, treated DH-82 cells displayed a lower percentage (<i>p =</i> 0.0316), intensity (<i>p =</i> 0.0002), and index of infection (<i>p =</i> 0.0022) when compared to non-treated cells. PHMB induced lower percentage of infection alone (<i>p =</i> 0.043), in combination with TLR9a (<i>p =</i> 0.043), and with TLR4a (<i>p =</i> 0.0213). Supernatants were collected and used to measure TNF-α and IL-6 levels. Increased TNF-α was observed after PHMB <i>plus</i> TLR4a, relative to uninfected and infected untreated macrophages (<i>p =</i> 0.043). PHMB combined with TLR4a shows promise as a potential anti-<i>L. infantum</i> drug combination, as well as inducer of proinflammatory response, as demonstrated by decreased infection and increased TNF-α production.
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