Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis

Abstract In order to develop an improved BCG vaccine against tuberculosis we have taken advantage of the adjuvant properties of a non-toxic derivative of Escherichia coli heat labile enterotoxin (LT), LTAK63. We have constructed rBCG strains expressing LTAK63 at different expression levels. Mice imm...

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Autores principales:	Ivan P. Nascimento, Dunia Rodriguez, Carina C. Santos, Eduardo P. Amaral, Henrique K. Rofatto, Ana P. Junqueira-Kipnis, Eduardo D. C. Gonçalves, Maria R. D’Império-Lima, Mario H. Hirata, Celio L. Silva, Nathalie Winter, Brigitte Gicquel, Kingston H. G. Mills, Mariagrazia Pizza, Rino Rappuoli, Luciana C. C. Leite
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df9d3306cb574c71b46f4ee32a1a4202
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spelling	oai:doaj.org-article:df9d3306cb574c71b46f4ee32a1a42022021-12-02T15:05:31ZRecombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis10.1038/s41598-017-02003-92045-2322https://doaj.org/article/df9d3306cb574c71b46f4ee32a1a42022017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02003-9https://doaj.org/toc/2045-2322Abstract In order to develop an improved BCG vaccine against tuberculosis we have taken advantage of the adjuvant properties of a non-toxic derivative of Escherichia coli heat labile enterotoxin (LT), LTAK63. We have constructed rBCG strains expressing LTAK63 at different expression levels. Mice immunized with BCG expressing low levels of LTAK63 (rBCG-LTAK63lo) showed higher Th1 cytokines and IL-17 in the lungs, and when challenged intratracheally with Mycobacterium tuberculosis displayed a 2.0–3.0 log reduction in CFU as compared to wild type BCG. Histopathological analysis of lung tissues from protected mice revealed a reduced inflammatory response. Immunization with rBCG-LTAK63lo also protected against a 100-fold higher challenge dose. Mice immunized with rBCG-LTAK63lo produced an increase in TGF-β as compared with BCG after challenge, with a corresponding reduction in Th1 and Th17 cytokines, as determined by Real Time RT-PCR. Furthermore, rBCG-LTAK63lo also displays protection against challenge with a highly virulent Beijing isolate. Our findings suggest that BCG with low-level expression of the LTAK63 adjuvant induces a stronger immune response in the lungs conferring higher levels of protection, and a novel mechanism subsequently triggers a regulatory immune response, which then limits the pathology. The rBCG-LTAK63lo strain can be the basis of an improved vaccine against tuberculosis.Ivan P. NascimentoDunia RodriguezCarina C. SantosEduardo P. AmaralHenrique K. RofattoAna P. Junqueira-KipnisEduardo D. C. GonçalvesMaria R. D’Império-LimaMario H. HirataCelio L. SilvaNathalie WinterBrigitte GicquelKingston H. G. MillsMariagrazia PizzaRino RappuoliLuciana C. C. LeiteNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ivan P. Nascimento Dunia Rodriguez Carina C. Santos Eduardo P. Amaral Henrique K. Rofatto Ana P. Junqueira-Kipnis Eduardo D. C. Gonçalves Maria R. D’Império-Lima Mario H. Hirata Celio L. Silva Nathalie Winter Brigitte Gicquel Kingston H. G. Mills Mariagrazia Pizza Rino Rappuoli Luciana C. C. Leite Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis
description	Abstract In order to develop an improved BCG vaccine against tuberculosis we have taken advantage of the adjuvant properties of a non-toxic derivative of Escherichia coli heat labile enterotoxin (LT), LTAK63. We have constructed rBCG strains expressing LTAK63 at different expression levels. Mice immunized with BCG expressing low levels of LTAK63 (rBCG-LTAK63lo) showed higher Th1 cytokines and IL-17 in the lungs, and when challenged intratracheally with Mycobacterium tuberculosis displayed a 2.0–3.0 log reduction in CFU as compared to wild type BCG. Histopathological analysis of lung tissues from protected mice revealed a reduced inflammatory response. Immunization with rBCG-LTAK63lo also protected against a 100-fold higher challenge dose. Mice immunized with rBCG-LTAK63lo produced an increase in TGF-β as compared with BCG after challenge, with a corresponding reduction in Th1 and Th17 cytokines, as determined by Real Time RT-PCR. Furthermore, rBCG-LTAK63lo also displays protection against challenge with a highly virulent Beijing isolate. Our findings suggest that BCG with low-level expression of the LTAK63 adjuvant induces a stronger immune response in the lungs conferring higher levels of protection, and a novel mechanism subsequently triggers a regulatory immune response, which then limits the pathology. The rBCG-LTAK63lo strain can be the basis of an improved vaccine against tuberculosis.
format	article
author	Ivan P. Nascimento Dunia Rodriguez Carina C. Santos Eduardo P. Amaral Henrique K. Rofatto Ana P. Junqueira-Kipnis Eduardo D. C. Gonçalves Maria R. D’Império-Lima Mario H. Hirata Celio L. Silva Nathalie Winter Brigitte Gicquel Kingston H. G. Mills Mariagrazia Pizza Rino Rappuoli Luciana C. C. Leite
author_facet	Ivan P. Nascimento Dunia Rodriguez Carina C. Santos Eduardo P. Amaral Henrique K. Rofatto Ana P. Junqueira-Kipnis Eduardo D. C. Gonçalves Maria R. D’Império-Lima Mario H. Hirata Celio L. Silva Nathalie Winter Brigitte Gicquel Kingston H. G. Mills Mariagrazia Pizza Rino Rappuoli Luciana C. C. Leite
author_sort	Ivan P. Nascimento
title	Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis
title_short	Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis
title_full	Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis
title_fullStr	Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis
title_full_unstemmed	Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis
title_sort	recombinant bcg expressing ltak63 adjuvant induces superior protection against mycobacterium tuberculosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/df9d3306cb574c71b46f4ee32a1a4202
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Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis

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