The effects of polyhexamethylene biguanide (PHMB) and TLR agonists alone or as polyplex nanoparticles against Leishmania infantum promastigotes and amastigotes
Martínez-Orellana, Pamela (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Good, Liam (University of London. Royal Veterinary College (Hatfield, Regne Unit))
Solano Gallego, Laia (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Baxarias, Marta (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)

Data:	2020
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad AGL2015-68477
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Leishmaniosi ; TLR4 agonist ; TLR9 agonist ; PHMB ; Leishmania infantum ; Canine ; Macrophages
Publicat a:	Veterinary sciences, Vol. 7 Núm. 4 (2020) , p. 179, ISSN 2306-7381

DOI: 10.3390/vetsci7040179
PMID: 33202979

14 p, 7.3 MB

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