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

Virulence

Nityananda Chowdhury¹  JoAnn S. Roberts¹  Jaden S. Lee¹  Özlem Yilmaz² 

[1] Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC, US;Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC, US;Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, US;

关键词: Ectonucleotidase-CD73;    purinergic signaling;    opportunistic oral bacteria;    epithelial cells;    intracellular infection;    persistence;   

DOI  :  10.1080/21505594.2020.1763061

来源: Taylor & Francis

【 摘 要 】

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.

【 授权许可】

CC BY