Microbiome-mediated incapacitation of interferon lambda production in the oral mucosa
Carlos J. Rodriguez-Hernandez, Kevin J. Sokoloski, Kendall S. Stocke, Himabindu Dukka, Shunying Jin, Melissa A. Metzler, Konstantin Zaitsev, Boris Shpak, Daonan Shen, Daniel P. Miller, Maxim N. Artyomov, Richard J. Lamont, Juhi Bagaitkar
Abstract
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.