Streptococci are the dominant oral commensal organisms. They, along with putative
periodontal pathogens, normally colonize multiple oral tissue sites. An emerging
paradigm indicates that the host can distinguish between pathogenic and nonpathogenic
stimuli, and commensal bacteria could modulate expression of host genes to contribute to
mucosal tolerance. Here, I hypothesized that an oral commensal Streptococcus cristatus
can attenuate epithelial proinflammatory response to Fusobacterium nucleatum via
regulation of Toll-Like Receptor (TLR) signaling, as a mechanism for oral mucosal
tolerance to polymicrobial infection.
I first demonstrated that S. cristatus itself did not provoke IL-8 production in
epithelial cells, and it was able to inhibit IL-8 responses to several putative oral
pathogens including F. nucleatum. The inhibitory effect of S. cristatus on IL-8 was
independent of its viability and its coaggregation with F. nucleatum, was not related to
soluble bacterial products, and appeared to require bacterial contact with epithelial cells.
Similar effects were seen with several other species of oral streptococci.
Next, I performed pathway-specific microarray analysis to specifically monitor host
gene modulation by S. cristatus on a broad scale. I found that S. cristatus altered the F.
nucleatum–induced expression of a number of proinflammatory cytokine genes. Profiling
of TLR signaling related genes revealed that S. cristatus most significantly impacted the
downstream pathways, especially NF-κB, rather than altering TLRs and their adaptors
and interacting proteins.
Lastly, I examined the underlying mechanism(s) involved in the modulating effect of
S. cristatus by looking specifically at its impact on the nuclear factor kappaB (NF-κB)
pathway under the Toll-like receptor signaling background. I found that the IL-8
suppression by S. cristatus was coincident with the inhibition of NF-κB activation and
IκB-α degradation. Pre-incubation with TLR2 and TLR4 antibodies, however, did not
affect the epithelial response to either species alone or in combination.
I thus conclude that the oral commensal S. cristatus is not only tolerated by the host,
but also able to modulate host inflammatory response to pathogenic species through
inhibiting IκB-NF-κB signaling module. The anti-inflammatory effect of S. cristatus
might represent a regulatory mechanism present at the epithelial surface to tolerate
University of Minnesota Ph.D. dissertation. December 2009. Major: Oral Biology. Advisor: Joel D Rudney, PhD. 1 computer file (PDF); x, 168 pages, appendices pages 167-168.
Streptococcus cristatus modulates epithelial innate immune response through regulating nuclear factor-kappa B pathway..
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