Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum.
Identifieur interne : 000045 ( Main/Exploration ); précédent : 000044; suivant : 000046Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum.
Auteurs : Alba Martínez-Fl Rez [Espagne] ; Clara Martori [Espagne] ; Paula L. Monteagudo [Espagne, États-Unis] ; Fernando Rodriguez [Espagne] ; Jordi Alberola [Espagne] ; Alhelí Rodríguez-Cortés [Espagne]Source :
- Parasites & vectors [ 1756-3305 ] ; 2020.
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.
DOI: 10.1186/s13071-020-04165-4
PubMed: 32517744
PubMed Central: PMC7282043
Affiliations:
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Monteagudo</name><affiliation wicri:level="3"><nlm:affiliation>Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029</wicri:regionArea><wicri:noRegion>10029</wicri:noRegion></affiliation></author><author><name sortKey="Rodriguez, Fernando" sort="Rodriguez, Fernando" uniqKey="Rodriguez F" first="Fernando" last="Rodriguez">Fernando Rodriguez</name><affiliation wicri:level="3"><nlm:affiliation>Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></affiliation></author><author><name sortKey="Alberola, Jordi" sort="Alberola, Jordi" uniqKey="Alberola J" first="Jordi" last="Alberola">Jordi Alberola</name><affiliation wicri:level="4"><nlm:affiliation>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName><orgName type="university">Université autonome de Barcelone</orgName></affiliation></author><author><name sortKey="Rodriguez Cortes, Alheli" sort="Rodriguez Cortes, Alheli" uniqKey="Rodriguez Cortes A" first="Alhelí" last="Rodríguez-Cortés">Alhelí Rodríguez-Cortés</name><affiliation wicri:level="4"><nlm:affiliation>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. Alheli.Rodriguez@uab.cat.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona</wicri:regionArea><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName><orgName type="university">Université autonome de Barcelone</orgName></affiliation></author></analytic><series><title level="j">Parasites & vectors</title><idno type="eISSN">1756-3305</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>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.</p></div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">32517744</PMID><DateRevised><Year>2020</Year><Month>06</Month><Day>13</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1756-3305</ISSN><JournalIssue CitedMedium="Internet"><Volume>13</Volume><Issue>1</Issue><PubDate><Year>2020</Year><Month>Jun</Month><Day>09</Day></PubDate></JournalIssue><Title>Parasites & vectors</Title><ISOAbbreviation>Parasit Vectors</ISOAbbreviation></Journal><ArticleTitle>Sirolimus enhances the protection achieved by a DNA vaccine against Leishmania infantum.</ArticleTitle><Pagination><MedlinePgn>294</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1186/s13071-020-04165-4</ELocationID><Abstract><AbstractText Label="BACKGROUND" NlmCategory="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.</AbstractText><AbstractText Label="METHODS" NlmCategory="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.</AbstractText><AbstractText Label="RESULTS" NlmCategory="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.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Martínez-Flórez</LastName><ForeName>Alba</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martori</LastName><ForeName>Clara</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Monteagudo</LastName><ForeName>Paula L</ForeName><Initials>PL</Initials><AffiliationInfo><Affiliation>Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodriguez</LastName><ForeName>Fernando</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Centre de Recerca En Sanitat Animal (CReSA), Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Campus UAB, Bellaterra, 08193, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alberola</LastName><ForeName>Jordi</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodríguez-Cortés</LastName><ForeName>Alhelí</ForeName><Initials>A</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-3617-0119</Identifier><AffiliationInfo><Affiliation>Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. Alheli.Rodriguez@uab.cat.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>AGL2010-16678</GrantID><Agency>Ministerio de Economía y Competitividad</Agency><Country></Country></Grant><Grant><GrantID>AGL2014-56427-P</GrantID><Agency>Ministerio de Economía, Industria y Competitividad, Gobierno de España</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>06</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Parasit Vectors</MedlineTA><NlmUniqueID>101462774</NlmUniqueID><ISSNLinking>1756-3305</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">DNA vaccine</Keyword><Keyword MajorTopicYN="N">Hamster</Keyword><Keyword MajorTopicYN="N">Leishmania</Keyword><Keyword MajorTopicYN="N">Sirolimus</Keyword><Keyword MajorTopicYN="N">Vaccine</Keyword><Keyword MajorTopicYN="N">Visceral leishmaniasis</Keyword><Keyword MajorTopicYN="N">mTOR</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>12</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>06</Month><Day>02</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>6</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>6</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>6</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32517744</ArticleId><ArticleId 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name="Espagne"><region name="Catalogne"><name sortKey="Martinez Fl Rez, Alba" sort="Martinez Fl Rez, Alba" uniqKey="Martinez Fl Rez A" first="Alba" last="Martínez-Fl Rez">Alba Martínez-Fl Rez</name></region><name sortKey="Alberola, Jordi" sort="Alberola, Jordi" uniqKey="Alberola J" first="Jordi" last="Alberola">Jordi Alberola</name><name sortKey="Martori, Clara" sort="Martori, Clara" uniqKey="Martori C" first="Clara" last="Martori">Clara Martori</name><name sortKey="Monteagudo, Paula L" sort="Monteagudo, Paula L" uniqKey="Monteagudo P" first="Paula L" last="Monteagudo">Paula L. Monteagudo</name><name sortKey="Rodriguez Cortes, Alheli" sort="Rodriguez Cortes, Alheli" uniqKey="Rodriguez Cortes A" first="Alhelí" last="Rodríguez-Cortés">Alhelí Rodríguez-Cortés</name><name sortKey="Rodriguez, Fernando" sort="Rodriguez, Fernando" uniqKey="Rodriguez F" first="Fernando" last="Rodriguez">Fernando Rodriguez</name></country><country name="États-Unis"><noRegion><name sortKey="Monteagudo, Paula L" sort="Monteagudo, Paula L" uniqKey="Monteagudo P" first="Paula L" last="Monteagudo">Paula L. Monteagudo</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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