Abstract
Dogs are the main reservoir for Leishmania infantum, 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 L. infantum. Susceptibility of L. infantum promastigotes to PHMB, miltefosine, and allopurinol was performed, and the half-maximum inhibitory concentrations (IC50) 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 IC50 values of L. infantum 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 (p = 0.0316), intensity (p = 0.0002), and index of infection (p = 0.0022) when compared to non-treated cells. PHMB induced lower percentage of infection alone (p = 0.043), in combination with TLR9a (p = 0.043), and with TLR4a (p = 0.0213). Supernatants were collected and used to measure TNF-α and IL-6 levels. Increased TNF-α was observed after PHMB plus TLR4a, relative to uninfected and infected untreated macrophages (p = 0.043). PHMB combined with TLR4a shows promise as a potential anti-L. infantum drug combination, as well as inducer of proinflammatory response, as demonstrated by decreased infection and increased TNF-α production.
Highlights
Leishmaniases are a group of vector-borne infectious diseases in humans and animals caused by different species of Leishmania [1,2]
Polyhexamethylene biguanide (PHMB) combined with TLR4a shows promise as a potential anti-L. infantum drug combination, as well as inducer of proinflammatory response, as demonstrated by decreased infection and increased TNF-α production
In order to elucidate the in vitro antileishmanial properties of PHMB against L. infantum, here we studied the infection profile and proinflammatory cytokines produced by infected DH-82 cells after treatment with PHMB alone or as polyplex nanoparticles containing TLR4 or TLR9 agonists
Summary
Leishmaniases are a group of vector-borne infectious diseases in humans and animals caused by different species of Leishmania [1,2]. The genus Leishmania has a digenetic life cycle with two distinct stages recognized. An elongated shape and long flagella characterize the promastigote stage. Promastigotes are further subdivided into procyclic promastigotes that multiply in the gut of blood feeding sandfly phlebotomine and infective metacyclic promastigotes, housed in the mouth and anterior gut of the sand fly vector [3]. The parasite continues to differentiate in the mammalian host as a non-motile amastigote with rounded or oval shaped cell that lacks flagella. The amastigote stage commonly resides and replicates within the phagolysosome of macrophages [4]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.