Innate immunity is present from birth and represents the inherited resistance to infection. Microbial infection is detected by pattern-recognition receptors (PRRs) through recognition of microbe-associated molecular patterns (MAMPs). Since MAMPs are conserved in a wide range of pathogenic or commensal organisms, it is not clear how PRR-MAMP interactions per se lead to differential host responses to pathogens and commensals. This application proposes that pathogens exploit selective pattern recognition pathways in ways that perturb the otherwise homeostatic PRR-MAMP interactions, leading to chronic persistence of the pathogen and nonproductive inflammation. This outcome is detrimental especially to the elderly host due to age-related alterations in pattern-recognition mechanisms. In this regard, it is proposed that pathway-specific alterations in innate recognition render the aging innate immune system more amenable to exploitation by pathogens than its younger counterpart. Taking advantage of the accessibility and relevance of the oral cavity in host-microbial interactions, these concepts will be investigated in the context of periodontitis and the model pathogen Porphyromonas gingivalis. P. gingivalis interacts via its surface fimbriae with the CD14/Toll-like receptor 2 recognition complex and induces phosphatidylinositol-3-kinase signaling for activating the adhesive capacity of CR3, a monocytic beta2 integrin with PRR capabilities. Although this proadhesive pathway promotes the migratory activity of monocytes, it has surprisingly been co-opted by P. gingivalis for exploiting CR3. By means of immunological, genetic, and biophysical techniques, as well as a mouse periodontitis model, these studies will test the hypothesis that the interaction of P. gingivalis with activated CR3 leads to pathogen internalization, suppression of normal defense clearing mechanisms, inhibition of apoptosis, and promotion of intracellular persistence. Moreover, it is hypothesized that the inducibility of this co-opted pathway becomes higher with age leading to enhanced immune evasion by P. gingivalis and potentially increased periodontal disease activity. This study has been designed not only for answering fundamental questions in innate immunity, but also for facilitating the development of novel immunomodulatory concepts at a translational level. Indeed, only by knowing how the innate response is deregulated by pathogens, could effective immunomodulatory strategies be implemented for redirecting the oral mucosal immune defense to the benefit of the elderly host. While the proposed experimental model focuses on a periodontal pathogen, the fundamental concept of immune evasion by corruption of PRR function and how this process changes with advancing age may be applicable to infections of less accessible mucosal tracts such as the respiratory, gastrointestinal, and genitourinary tracts.
NIH ExPorter
NIH ExPorter