Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hy...

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Autores principales:	Courtney E McDougal, Zachary T Morrow, Tighe Christopher, Seonyoung Kim, Drake Carter, David M Stevenson, Daniel Amador-Noguez, Mark J Miller, John-Demian Sauer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/70d5aed845d64ce69478e83c864f8843
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spelling	oai:doaj.org-article:70d5aed845d64ce69478e83c864f88432021-12-02T20:00:07ZPhagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.1553-73661553-737410.1371/journal.ppat.1009493https://doaj.org/article/70d5aed845d64ce69478e83c864f88432021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009493https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2) is essential for optimal L. monocytogenes T-cell priming. Here, we demonstrate that vacuole-constrained L. monocytogenes elicit reduced PGE2 production compared to wild-type strains in macrophages and dendritic cells ex vivo. In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE2 production early during infection whereas vacuole-constrained strains fail to induce PGE2 over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2+ or CD11c+ cells produce less PGE2, suggesting these cell subsets contribute to PGE2 levels in vivo, while depletion of phagocytes with clodronate abolishes PGE2 production completely. Taken together, this work demonstrates that optimal PGE2 production by phagocytes depends on L. monocytogenes access to the cytosol, suggesting that one reason cytosolic access is required to prime CD8+ T-cell responses may be to facilitate production of PGE2.Courtney E McDougalZachary T MorrowTighe ChristopherSeonyoung KimDrake CarterDavid M StevensonDaniel Amador-NoguezMark J MillerJohn-Demian SauerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009493 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Courtney E McDougal Zachary T Morrow Tighe Christopher Seonyoung Kim Drake Carter David M Stevenson Daniel Amador-Noguez Mark J Miller John-Demian Sauer Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.
description	Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2) is essential for optimal L. monocytogenes T-cell priming. Here, we demonstrate that vacuole-constrained L. monocytogenes elicit reduced PGE2 production compared to wild-type strains in macrophages and dendritic cells ex vivo. In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE2 production early during infection whereas vacuole-constrained strains fail to induce PGE2 over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2+ or CD11c+ cells produce less PGE2, suggesting these cell subsets contribute to PGE2 levels in vivo, while depletion of phagocytes with clodronate abolishes PGE2 production completely. Taken together, this work demonstrates that optimal PGE2 production by phagocytes depends on L. monocytogenes access to the cytosol, suggesting that one reason cytosolic access is required to prime CD8+ T-cell responses may be to facilitate production of PGE2.
format	article
author	Courtney E McDougal Zachary T Morrow Tighe Christopher Seonyoung Kim Drake Carter David M Stevenson Daniel Amador-Noguez Mark J Miller John-Demian Sauer
author_facet	Courtney E McDougal Zachary T Morrow Tighe Christopher Seonyoung Kim Drake Carter David M Stevenson Daniel Amador-Noguez Mark J Miller John-Demian Sauer
author_sort	Courtney E McDougal
title	Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.
title_short	Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.
title_full	Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.
title_fullStr	Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.
title_full_unstemmed	Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.
title_sort	phagocytes produce prostaglandin e2 in response to cytosolic listeria monocytogenes.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/70d5aed845d64ce69478e83c864f8843
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_version_	1718375728759701504

Phagocytes produce prostaglandin E2 in response to cytosolic Listeria monocytogenes.

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