Signaling crosstalk or communication between components of the innate immune system, such as Toll-like receptors (TLRs) and complement, normally serves to coordinate the host immune response to infection. However, the periodontal bacterium Porphyromonas gingivalis adeptly exploits signaling crosstalk to escape immune elimination. Intriguingly, the capacity of P. gingivalis to manipulate the host response enables it to act as a """"""""keystone pathogen"""""""", that is, to alter the numbers and composition of the entire microbial community leading to dysbiosis and periodontitis, a chronic inflammatory condition of the tooth-supporting tissues with an adverse impact on systemic health. Although the keystone pathogen concept has revolutionized the fundamental understanding of periodontitis, it has generated new puzzling questions: The molecular mechanism(s) by which P. gingivalis can selectively inhibit immune elimination without inhibiting inflammation remains a mystery (Question [Q]-1). Subtle manipulation of host signaling pathways is a matter of life and death for P. gingivalis and dependent co-habiting bacteria~ if P. gingivalis simply caused immunosuppression, this would inhibit bacterial killing but would deprive the bacteria of critical nutrients derived from inflammatory tissue breakdown. Another intriguing question is why the presence of a keystone pathogen such as P. gingivalis does not always lead to periodontitis (Q-2). In this regard, P. gingivalis may occasionally be detected in the """"""""normal"""""""" periodontal microbiota of healthy individuals. The overarching hypothesis of this proposal is that the virulence of P. gingivalis acquires relevance in the context of a synergistic microbial community and a susceptible host, both of which are required for the expression of pathogenicity.
In Specific Aim 1 (addressing Q-1), it is proposed that P. gingivalis exploits complement C5a receptor to disassociate a host-protective TLR2-MyD88 pathway from a TLR2-PI3K pathway that mediates non-protective inflammation favoring the bacteria. This investigation will utilize established in vitro and in vivo models of P. gingivalis interactions with neutrophils, which play a major role in periodontitis and form the majority of leukocytes recruited to the gingival crevice.
In Specific Aim 2 (addressing Q-2), it is proposed that specific host pathways determine host susceptibility to P. gingivalis-induced dysbiosis and periodontitis. The underlying rationale is that there may be P. gingivalis-harboring healthy individuals who, by virtue of their intrinsic immuno-inflammatory status, can resist or tolerate the conversion of the periodontal microbiota from a symbiotic to a dysbiotic state. To this end, we will use animal models of periodontitis including mice homozygous or heterozygous for specific immune response genes, as a model of host response-related genetic variation. The dissection of mechanisms that stabilize or counteract dysbiotic microbial communities may offer an in-depth understanding of periodontal pathogenesis and lead to innovative and targeted treatment modalities.
Periodontitis is one of the most common chronic disorders of microbial origin in humans and exerts an adverse impact on systemic health. The objective of this proposal is to dissect the mechanisms whereby P. gingivalis acts as a stabilizing element of dysbiotic, disease-provoking microbial communities, and to elucidate host response pathways that regulate dysbiosis. This may offer an in-depth understanding of periodontal pathogenesis and facilitate the development of innovative treatment modalities, on the basis of targets identified in this proposal.
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