Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease

Abstract The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent...

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Autores principales:	Nandadeva Lokugamage, Imran H. Chowdhury, Ronald J. Biediger, Robert V. Market, Sayadeth Khounlo, Navin D. Warier, Shen-An Hwang, Jeffrey K. Actor, Darren G. Woodside, Upendra Marathi, Peter Vanderslice, Nisha Jain Garg
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/fa56993f549b4cbda0b8eb8236c01b18
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spelling	oai:doaj.org-article:fa56993f549b4cbda0b8eb8236c01b182021-12-02T17:41:15ZUse of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease10.1038/s41541-021-00378-52059-0105https://doaj.org/article/fa56993f549b4cbda0b8eb8236c01b182021-09-01T00:00:00Zhttps://doi.org/10.1038/s41541-021-00378-5https://doaj.org/toc/2059-0105Abstract The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent of antigen. 7HP349 directly activates integrin cell adhesion receptors crucial for the generation of an immune response. When delivered systemically in a model of Chagas disease following immunization with a DNA subunit vaccine encoding candidate T. cruzi antigens, TcG2 and TcG4, 7HP349 enhanced the vaccine efficacy in both prophylactic and therapeutic settings. In a prophylactic setting, mice immunized with 7HP349 adjuvanted vaccine exhibited significantly improved control of acute parasite burden in cardiac and skeletal muscle as compared to vaccination alone. When administered with vaccine therapeutically, parasite burden was again decreased, with the greatest adjuvant effect of 7HP349 being noted in skeletal muscle. In both settings, adjuvantation with 7HP349 was effective in decreasing pathological inflammatory infiltrate, improving the integrity of tissue, and controlling tissue fibrosis in the heart and skeletal muscle of acutely and chronically infected Chagas mice. The positive effects correlated with increased splenic frequencies of CD8+T effector cells and an increase in the production of IFN-γ and cytolytic molecules (perforin and granzyme) by the CD4+ and CD8+ effector and central memory subsets in response to challenge infection. This demonstrates that 7HP349 can serve as a systemically administered adjuvant to enhance T cell-mediated immune responses to vaccines. This approach could be applied to numerous vaccines with no reformulation of existing stockpiles.Nandadeva LokugamageImran H. ChowdhuryRonald J. BiedigerRobert V. MarketSayadeth KhounloNavin D. WarierShen-An HwangJeffrey K. ActorDarren G. WoodsideUpendra MarathiPeter VandersliceNisha Jain GargNature PortfolioarticleImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Vaccines, Vol 6, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Nandadeva Lokugamage Imran H. Chowdhury Ronald J. Biediger Robert V. Market Sayadeth Khounlo Navin D. Warier Shen-An Hwang Jeffrey K. Actor Darren G. Woodside Upendra Marathi Peter Vanderslice Nisha Jain Garg Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
description	Abstract The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent of antigen. 7HP349 directly activates integrin cell adhesion receptors crucial for the generation of an immune response. When delivered systemically in a model of Chagas disease following immunization with a DNA subunit vaccine encoding candidate T. cruzi antigens, TcG2 and TcG4, 7HP349 enhanced the vaccine efficacy in both prophylactic and therapeutic settings. In a prophylactic setting, mice immunized with 7HP349 adjuvanted vaccine exhibited significantly improved control of acute parasite burden in cardiac and skeletal muscle as compared to vaccination alone. When administered with vaccine therapeutically, parasite burden was again decreased, with the greatest adjuvant effect of 7HP349 being noted in skeletal muscle. In both settings, adjuvantation with 7HP349 was effective in decreasing pathological inflammatory infiltrate, improving the integrity of tissue, and controlling tissue fibrosis in the heart and skeletal muscle of acutely and chronically infected Chagas mice. The positive effects correlated with increased splenic frequencies of CD8+T effector cells and an increase in the production of IFN-γ and cytolytic molecules (perforin and granzyme) by the CD4+ and CD8+ effector and central memory subsets in response to challenge infection. This demonstrates that 7HP349 can serve as a systemically administered adjuvant to enhance T cell-mediated immune responses to vaccines. This approach could be applied to numerous vaccines with no reformulation of existing stockpiles.
format	article
author	Nandadeva Lokugamage Imran H. Chowdhury Ronald J. Biediger Robert V. Market Sayadeth Khounlo Navin D. Warier Shen-An Hwang Jeffrey K. Actor Darren G. Woodside Upendra Marathi Peter Vanderslice Nisha Jain Garg
author_facet	Nandadeva Lokugamage Imran H. Chowdhury Ronald J. Biediger Robert V. Market Sayadeth Khounlo Navin D. Warier Shen-An Hwang Jeffrey K. Actor Darren G. Woodside Upendra Marathi Peter Vanderslice Nisha Jain Garg
author_sort	Nandadeva Lokugamage
title	Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
title_short	Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
title_full	Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
title_fullStr	Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
title_full_unstemmed	Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease
title_sort	use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling chagas disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fa56993f549b4cbda0b8eb8236c01b18
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Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease

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