TY - JOUR
T1 - Microbiome-mediated incapacitation of interferon lambda production in the oral mucosa
AU - Rodriguez-Hernandez, Carlos J.
AU - Sokoloski, Kevin J.
AU - Stocke, Kendall S.
AU - Dukka, Himabindu
AU - Jin, Shunying
AU - Metzler, Melissa A.
AU - Zaitsev, Konstantin
AU - Shpak, Boris
AU - Shen, Daonan
AU - Miller, Daniel P.
AU - Artyomov, Maxim N.
AU - Lamont, Richard J.
AU - Bagaitkar, Juhi
N1 - Funding Information:
performed with the assistance of the University of Louisville Genomics Facility, which is supported by NIH P20GM103436 (KY IDeA Networks of Biomedical Research Excellence), the J. G. Brown Cancer Center, and user fees. K.Z. was supported by Government of Russian Federation (Grant No. 08-08).
Funding Information:
ACKNOWLEDGMENTS. These studies were funded by National Institute of Dental and Craniofacial Research (NIDCR) Grant Nos. DE028031 and DE028296 to J.B.; National Institute of General Medical Sciences grant GM125504 to J.B., K.J.S., and R.J.L.; and NIDCR grants DE011111, DE012505, DE023193, and DE017921 to R.J.L.; Part of this work was
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/12/21
Y1 - 2021/12/21
N2 - Here, we show that Porphyromonas gingivalis (Pg), an endogenous oral pathogen, dampens all aspects of interferon (IFN) signaling in a manner that is strikingly similar to IFN suppression employed by multiple viral pathogens. Pg suppressed IFN production by down-regulating several IFN regulatory factors (IRFs 1, 3, 7, and 9), proteolytically degrading STAT1 and suppressing the nuclear translocation of the ISGF3 complex, resulting in profound and systemic repression of multiple interferon-stimulated genes. Pg-induced IFN paralysis was not limited to murine models but was also observed in the oral tissues of human periodontal disease patients, where overabundance of Pg correlated with suppressed IFN generation. Mechanistically, multiple virulence factors and secreted proteases produced by Pg transcriptionally suppressed IFN promoters and also cleaved IFN receptors, making cells refractory to exogenous IFN and inducing a state of broad IFN paralysis. Thus, our data show a bacterial pathogen with equivalence to viruses in the down-regulation of host IFN signaling.
AB - Here, we show that Porphyromonas gingivalis (Pg), an endogenous oral pathogen, dampens all aspects of interferon (IFN) signaling in a manner that is strikingly similar to IFN suppression employed by multiple viral pathogens. Pg suppressed IFN production by down-regulating several IFN regulatory factors (IRFs 1, 3, 7, and 9), proteolytically degrading STAT1 and suppressing the nuclear translocation of the ISGF3 complex, resulting in profound and systemic repression of multiple interferon-stimulated genes. Pg-induced IFN paralysis was not limited to murine models but was also observed in the oral tissues of human periodontal disease patients, where overabundance of Pg correlated with suppressed IFN generation. Mechanistically, multiple virulence factors and secreted proteases produced by Pg transcriptionally suppressed IFN promoters and also cleaved IFN receptors, making cells refractory to exogenous IFN and inducing a state of broad IFN paralysis. Thus, our data show a bacterial pathogen with equivalence to viruses in the down-regulation of host IFN signaling.
KW - Interferon lambda
KW - Oral epithelial cells
KW - Periodontitis
KW - Porphyromonas gingivalis
KW - Viral infection
UR - http://www.scopus.com/inward/record.url?scp=85122581231&partnerID=8YFLogxK
U2 - 10.1073/pnas.2105170118
DO - 10.1073/pnas.2105170118
M3 - Article
C2 - 34921113
AN - SCOPUS:85122581231
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
M1 - e2105170118
ER -