TY - JOUR
T1 - Regulation of olfactomedin 4 by Porphyromonas gingivalis in a community context
AU - Fitzsimonds, Zackary R.
AU - Liu, Chengcheng
AU - Stocke, Kendall S.
AU - Yakoumatos, Lan
AU - Shumway, Brian
AU - Miller, Daniel P.
AU - Artyomov, Maxim N.
AU - Bagaitkar, Juhi
AU - Lamont, Richard J.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to International Society for Microbial Ecology.
PY - 2021/9
Y1 - 2021/9
N2 - At mucosal barriers, the virulence of microbial communities reflects the outcome of both dysbiotic and eubiotic interactions with the host, with commensal species mitigating or potentiating the action of pathogens. We examined epithelial responses to the oral pathogen Porphyromonas gingivalis as a monoinfection and in association with a community partner, Streptococcus gordonii. RNA-Seq of oral epithelial cells showed that the Notch signaling pathway, including the downstream effector olfactomedin 4 (OLFM4), was differentially regulated by P. gingivalis alone; however, regulation was overridden by S. gordonii. OLFM4 was required for epithelial cell migratory, proliferative and inflammatory responses to P. gingivalis. Activation of Notch signaling was induced through increased expression of the Notch1 receptor and the Jagged1 (Jag1) agonist. In addition, Jag1 was released in response to P. gingivalis, leading to paracrine activation. Following Jag1-Notch1 engagement, the Notch1 extracellular domain was cleaved by P. gingivalis gingipain proteases. Antagonism by S. gordonii involved inhibition of gingipain activity by secreted hydrogen peroxide. The results establish a novel mechanism by which P. gingivalis modulates epithelial cell function which is dependent on community context. These interrelationships have relevance for innate inflammatory responses and epithelial cell fate decisions in oral health and disease.
AB - At mucosal barriers, the virulence of microbial communities reflects the outcome of both dysbiotic and eubiotic interactions with the host, with commensal species mitigating or potentiating the action of pathogens. We examined epithelial responses to the oral pathogen Porphyromonas gingivalis as a monoinfection and in association with a community partner, Streptococcus gordonii. RNA-Seq of oral epithelial cells showed that the Notch signaling pathway, including the downstream effector olfactomedin 4 (OLFM4), was differentially regulated by P. gingivalis alone; however, regulation was overridden by S. gordonii. OLFM4 was required for epithelial cell migratory, proliferative and inflammatory responses to P. gingivalis. Activation of Notch signaling was induced through increased expression of the Notch1 receptor and the Jagged1 (Jag1) agonist. In addition, Jag1 was released in response to P. gingivalis, leading to paracrine activation. Following Jag1-Notch1 engagement, the Notch1 extracellular domain was cleaved by P. gingivalis gingipain proteases. Antagonism by S. gordonii involved inhibition of gingipain activity by secreted hydrogen peroxide. The results establish a novel mechanism by which P. gingivalis modulates epithelial cell function which is dependent on community context. These interrelationships have relevance for innate inflammatory responses and epithelial cell fate decisions in oral health and disease.
UR - http://www.scopus.com/inward/record.url?scp=85103034475&partnerID=8YFLogxK
U2 - 10.1038/s41396-021-00956-4
DO - 10.1038/s41396-021-00956-4
M3 - Article
C2 - 33731837
AN - SCOPUS:85103034475
VL - 15
SP - 2627
EP - 2642
JO - ISME Journal
JF - ISME Journal
SN - 1751-7362
IS - 9
ER -