Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum
Abstract Background 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 trea...
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| Format: | Article |
| Language: | English |
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BMC
2020-06-01
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| Series: | Parasites & Vectors |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13071-020-04165-4 |
| _version_ | 1818610776995266560 |
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| author | Alba Martínez-Flórez Clara Martori Paula L. Monteagudo Fernando Rodriguez Jordi Alberola Alhelí Rodríguez-Cortés |
| author_facet | Alba Martínez-Flórez Clara Martori Paula L. Monteagudo Fernando Rodriguez Jordi Alberola Alhelí Rodríguez-Cortés |
| author_sort | Alba Martínez-Flórez |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-16T15:19:49Z |
| format | Article |
| id | doaj.art-b376b81a190740d5817a68c4efd98365 |
| institution | Directory Open Access Journal |
| issn | 1756-3305 |
| language | English |
| last_indexed | 2024-12-16T15:19:49Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Parasites & Vectors |
| spelling | doaj.art-b376b81a190740d5817a68c4efd983652022-12-21T22:26:40ZengBMCParasites & Vectors1756-33052020-06-0113111210.1186/s13071-020-04165-4Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantumAlba Martínez-Flórez0Clara Martori1Paula L. Monteagudo2Fernando Rodriguez3Jordi Alberola4Alhelí Rodríguez-Cortés5Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de BarcelonaDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de BarcelonaCentre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA)Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA)Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de BarcelonaDepartament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de BarcelonaAbstract Background 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s13071-020-04165-4LeishmaniaVaccineVisceral leishmaniasisHamsterSirolimusmTOR |
| spellingShingle | Alba Martínez-Flórez Clara Martori Paula L. Monteagudo Fernando Rodriguez Jordi Alberola Alhelí Rodríguez-Cortés Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum Parasites & Vectors Leishmania Vaccine Visceral leishmaniasis Hamster Sirolimus mTOR |
| title | Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum |
| title_full | Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum |
| title_fullStr | Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum |
| title_full_unstemmed | Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum |
| title_short | Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum |
| title_sort | sirolimus enhances the protection achieved by a dna vaccine against leishmania infantum |
| topic | Leishmania Vaccine Visceral leishmaniasis Hamster Sirolimus mTOR |
| url | http://link.springer.com/article/10.1186/s13071-020-04165-4 |
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