Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum
Martínez-Flórez, Alba (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Martori Muntsant, Clara (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Monteagudo, Paula L. (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica). Department of Microbiology)
Rodriguez, Fernando (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Alberola, Jordi (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Rodriguez-Cortes, Alheli (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)

Data:	2020
Resum:	Leishmaniases are a group of neglected tropical parasitic diseases, mainly affecting vulnerable populations of countries with poor socioeconomic status. Development of efficient vaccines is a priority due to the increasing incidence of drug resistance and toxicity to current treatments. In the search for a safe and efficient protective vaccine for human and dog visceral leishmaniases, we analyzed the suitability of the immunomodulatory drug sirolimus (SIR) to boost a preventive DNA vaccine against leishmaniasis. SIR is an already marketed drug that has been described to boost immune protection against different disease models and has also emerged as a promising therapeutic drug against L. major. Syrian hamsters were treated with SIR concomitantly with the administration of a DNA vaccine formulation consisting in four plasmids carrying the Leishmania genes LACK, TRYP, PAPLE22 and KMPII, respectively. Two weeks after the last vaccination, the animals were infected intraperitoneally with L. infantum parasites. Five weeks post-infection the parasite load was measured by real-time PCR in target tissues and immune response was evaluated by determining anti- Leishmania specific antibodies in combination with cytokine expression in the spleen. Our results show that the DNA vaccine itself efficiently reduced the burden of parasites in the skin (P = 0. 0004) and lymph nodes (P = 0. 0452). SIR administration also enhanced the protection by reducing the parasite load in the spleen (P = 0. 0004). Vaccinated animals with or without SIR co-treatment showed lower IFN-γ expression levels than those found in the spleen of control animals. mRNA expression levels of NOS2 and IL-10 were found to be significantly higher in the vaccinated plus SIR treated group. Co-administration of SIR enhances a DNA vaccination regimen against L. infantum, improving the reduction of parasite load in skin, lymph node and spleen. The analysis of immune markers in the spleen after challenge suggests that the trend to recover naïve levels of IFN-γ and IL-10, and the concurrent higher expression of NOS2, may be responsible for the protection induced by our vaccine co-administered with SIR.
Ajuts:	Ministerio de Ciencia e Innovación AGL2010-16678 Ministerio de Economía y Competitividad AGL2014-56427-P
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:	Leishmania ; Vaccine ; Visceral leishmaniasis ; Hamster ; Sirolimus ; Mtor ; DNA vaccine
Publicat a:	Parasites & vectors, Vol. 13 (june 2020) , ISSN 1756-3305

DOI: 10.1186/s13071-020-04165-4
PMID: 32517744

12 p, 1.3 MB

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