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An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice
Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis due to M. tuberculosis (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-p...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683161/ https://www.ncbi.nlm.nih.gov/pubmed/31396406 http://dx.doi.org/10.1038/s41541-019-0122-8 |
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author | Khan, Arshad Bakhru, Pearl Saikolappan, Sankaralingam Das, Kishore Soudani, Emily Singh, Christopher R. Estrella, Jaymie L. Zhang, Dekai Pasare, Chandrashekhar Ma, Yue Sun, Jianjun Wang, Jin Hunter, Robert L. Tony Eissa, N. Dhandayuthapani, Subramanian Jagannath, Chinnaswamy |
author_facet | Khan, Arshad Bakhru, Pearl Saikolappan, Sankaralingam Das, Kishore Soudani, Emily Singh, Christopher R. Estrella, Jaymie L. Zhang, Dekai Pasare, Chandrashekhar Ma, Yue Sun, Jianjun Wang, Jin Hunter, Robert L. Tony Eissa, N. Dhandayuthapani, Subramanian Jagannath, Chinnaswamy |
author_sort | Khan, Arshad |
collection | PubMed |
description | Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis due to M. tuberculosis (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-presenting cells (APCs) affecting T-cell activation. To bypass these defects, an autophagy-inducing, TLR-2 activating C5 peptide from Mtb-derived CFP-10 protein was overexpressed in BCG in combination with Ag85B. Recombinant BCG(85C5) induced a robust MHC-II-dependent antigen presentation to CD4 T cells in vitro, and elicited stronger T(H)1 cytokines (IL-12, IL-1β, and TNFα) from APCs of C57Bl/6 mice increasing phosphorylation of p38MAPK and ERK. BCG(85C5) also enhanced MHC-II surface expression of MΦs by inhibiting MARCH1 ubiquitin ligase that degrades MHC-II. BCG(85C5) infected APCs from MyD88 or TLR-2 knockout mice showed decreased antigen presentation. Furthermore, BCG(85C5) induced LC3-dependent autophagy in macrophages increasing antigen presentation. Consistent with in vitro effects, BCG(85C5) markedly expanded both effector and central memory T cells in C57Bl/6 mice protecting them against both primary aerosol infection with Mtb and reinfection, but was less effective among TLR-2 knockout mice. Thus, BCG(85C5) induces stronger and longer lasting immunity, and is better than BCG against tuberculosis of mice. |
format | Online Article Text |
id | pubmed-6683161 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66831612019-08-08 An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice Khan, Arshad Bakhru, Pearl Saikolappan, Sankaralingam Das, Kishore Soudani, Emily Singh, Christopher R. Estrella, Jaymie L. Zhang, Dekai Pasare, Chandrashekhar Ma, Yue Sun, Jianjun Wang, Jin Hunter, Robert L. Tony Eissa, N. Dhandayuthapani, Subramanian Jagannath, Chinnaswamy NPJ Vaccines Article Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis due to M. tuberculosis (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-presenting cells (APCs) affecting T-cell activation. To bypass these defects, an autophagy-inducing, TLR-2 activating C5 peptide from Mtb-derived CFP-10 protein was overexpressed in BCG in combination with Ag85B. Recombinant BCG(85C5) induced a robust MHC-II-dependent antigen presentation to CD4 T cells in vitro, and elicited stronger T(H)1 cytokines (IL-12, IL-1β, and TNFα) from APCs of C57Bl/6 mice increasing phosphorylation of p38MAPK and ERK. BCG(85C5) also enhanced MHC-II surface expression of MΦs by inhibiting MARCH1 ubiquitin ligase that degrades MHC-II. BCG(85C5) infected APCs from MyD88 or TLR-2 knockout mice showed decreased antigen presentation. Furthermore, BCG(85C5) induced LC3-dependent autophagy in macrophages increasing antigen presentation. Consistent with in vitro effects, BCG(85C5) markedly expanded both effector and central memory T cells in C57Bl/6 mice protecting them against both primary aerosol infection with Mtb and reinfection, but was less effective among TLR-2 knockout mice. Thus, BCG(85C5) induces stronger and longer lasting immunity, and is better than BCG against tuberculosis of mice. Nature Publishing Group UK 2019-08-05 /pmc/articles/PMC6683161/ /pubmed/31396406 http://dx.doi.org/10.1038/s41541-019-0122-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Khan, Arshad Bakhru, Pearl Saikolappan, Sankaralingam Das, Kishore Soudani, Emily Singh, Christopher R. Estrella, Jaymie L. Zhang, Dekai Pasare, Chandrashekhar Ma, Yue Sun, Jianjun Wang, Jin Hunter, Robert L. Tony Eissa, N. Dhandayuthapani, Subramanian Jagannath, Chinnaswamy An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice |
title | An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice |
title_full | An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice |
title_fullStr | An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice |
title_full_unstemmed | An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice |
title_short | An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice |
title_sort | autophagy-inducing and tlr-2 activating bcg vaccine induces a robust protection against tuberculosis in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683161/ https://www.ncbi.nlm.nih.gov/pubmed/31396406 http://dx.doi.org/10.1038/s41541-019-0122-8 |
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