Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells

Cell surface nucleotide-metabolizing enzyme, ectonucleotidase-CD73, has emerged as a central component of the cellular homeostatic-machinery that counterbalances the danger-molecule (extracellular-ATP)-driven proinflammatory response in immune cells. While the importance of CD73 in microbial host fi...

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Autores principales:	Jaden S. Lee, Nityananda Chowdhury, JoAnn S. Roberts, Özlem Yilmaz
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2020
Materias:	ectonucleotidase-cd73 purinergic signaling opportunistic oral bacteria epithelial cells intracellular infection persistence Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/9e982bd611154620955d119b2d02c9bc
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spelling	oai:doaj.org-article:9e982bd611154620955d119b2d02c9bc2021-11-17T14:21:58ZHost surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells2150-55942150-560810.1080/21505594.2020.1763061https://doaj.org/article/9e982bd611154620955d119b2d02c9bc2020-12-01T00:00:00Zhttp://dx.doi.org/10.1080/21505594.2020.1763061https://doaj.org/toc/2150-5594https://doaj.org/toc/2150-5608Cell surface nucleotide-metabolizing enzyme, ectonucleotidase-CD73, has emerged as a central component of the cellular homeostatic-machinery that counterbalances the danger-molecule (extracellular-ATP)-driven proinflammatory response in immune cells. While the importance of CD73 in microbial host fitness and symbiosis is gradually being unraveled, there remains a significant gap in knowledge of CD73 and its putative role in epithelial cells. Here, we depict a novel host-pathogen adaptation mechanism where CD73 takes a center role in the intracellular persistence of Porphyromonas gingivalis, a major colonizer of oral mucosa, using human primary gingival epithelial cell (GEC) system. Temporal analyses revealed, upon invasion into the GECs, P. gingivalis can significantly elevate the host-surface CD73 activity and expression. The enhanced and active CD73 significantly increases P. gingivalis intracellular growth in the presence of substrate-AMP and simultaneously acts as a negative regulator of reactive oxygen species (ROS) generation upon eATP treatment. The inhibition of CD73 by siRNA or by a specific inhibitor markedly increases ROS production. Moreover, CD73 and P. gingivalis cross-signaling significantly modulates pro-inflammatory interleukin-6 (IL-6) in the GECs. Conversely, exogenous treatment of the infected GECs with IL-6 suppresses the intracellular bacteria via amplified ROS generation. However, the decreased bacterial levels can be restored by overexpressing functionally active CD73. Together, these findings illuminate how the local extracellular-purine-metabolism, in which CD73 serves as a core molecular switch, can alter intracellular microbial colonization resistance. Further, host-adaptive pathogens such as P. gingivalis can target host ectonucleotidases to disarm specific innate defenses for successful intracellular persistence in mucosal epithelia.Jaden S. LeeNityananda ChowdhuryJoAnn S. RobertsÖzlem YilmazTaylor & Francis Grouparticleectonucleotidase-cd73purinergic signalingopportunistic oral bacteriaepithelial cellsintracellular infectionpersistenceInfectious and parasitic diseasesRC109-216ENVirulence, Vol 11, Iss 1, Pp 414-429 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	ectonucleotidase-cd73 purinergic signaling opportunistic oral bacteria epithelial cells intracellular infection persistence Infectious and parasitic diseases RC109-216
spellingShingle	ectonucleotidase-cd73 purinergic signaling opportunistic oral bacteria epithelial cells intracellular infection persistence Infectious and parasitic diseases RC109-216 Jaden S. Lee Nityananda Chowdhury JoAnn S. Roberts Özlem Yilmaz Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
description	Cell surface nucleotide-metabolizing enzyme, ectonucleotidase-CD73, has emerged as a central component of the cellular homeostatic-machinery that counterbalances the danger-molecule (extracellular-ATP)-driven proinflammatory response in immune cells. While the importance of CD73 in microbial host fitness and symbiosis is gradually being unraveled, there remains a significant gap in knowledge of CD73 and its putative role in epithelial cells. Here, we depict a novel host-pathogen adaptation mechanism where CD73 takes a center role in the intracellular persistence of Porphyromonas gingivalis, a major colonizer of oral mucosa, using human primary gingival epithelial cell (GEC) system. Temporal analyses revealed, upon invasion into the GECs, P. gingivalis can significantly elevate the host-surface CD73 activity and expression. The enhanced and active CD73 significantly increases P. gingivalis intracellular growth in the presence of substrate-AMP and simultaneously acts as a negative regulator of reactive oxygen species (ROS) generation upon eATP treatment. The inhibition of CD73 by siRNA or by a specific inhibitor markedly increases ROS production. Moreover, CD73 and P. gingivalis cross-signaling significantly modulates pro-inflammatory interleukin-6 (IL-6) in the GECs. Conversely, exogenous treatment of the infected GECs with IL-6 suppresses the intracellular bacteria via amplified ROS generation. However, the decreased bacterial levels can be restored by overexpressing functionally active CD73. Together, these findings illuminate how the local extracellular-purine-metabolism, in which CD73 serves as a core molecular switch, can alter intracellular microbial colonization resistance. Further, host-adaptive pathogens such as P. gingivalis can target host ectonucleotidases to disarm specific innate defenses for successful intracellular persistence in mucosal epithelia.
format	article
author	Jaden S. Lee Nityananda Chowdhury JoAnn S. Roberts Özlem Yilmaz
author_facet	Jaden S. Lee Nityananda Chowdhury JoAnn S. Roberts Özlem Yilmaz
author_sort	Jaden S. Lee
title	Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
title_short	Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
title_full	Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
title_fullStr	Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
title_full_unstemmed	Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
title_sort	host surface ectonucleotidase-cd73 and the opportunistic pathogen, porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells
publisher	Taylor & Francis Group
publishDate	2020
url	https://doaj.org/article/9e982bd611154620955d119b2d02c9bc
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Host surface ectonucleotidase-CD73 and the opportunistic pathogen, Porphyromonas gingivalis, cross-modulation underlies a new homeostatic mechanism for chronic bacterial survival in human epithelial cells

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