• IL-17/Th17 responses and their influence on oral microbial communities

      Abusleme, Loreto; Moutsopoulos, Niki (2017)
      T helper 17 (Th17) cells are key regulators of immunity and inflammation at mucosal surfaces. This T cell subset has been reported to mediate protective responses, but also immunopathology at the oral cavity. However, the requirements for Th17 cells to arise at this site remained minimally explored. Our initial objective was to examine the role of oral microbial communities in local Th17 induction, as the development of these cells had been shown to be determined by commensal bacteria at other barriers. To this end, we established assays to analyze the murine oral microbiome and found that Th17 accumulation occurred independently from microbial colonization at the oral mucosa, underlining the unique properties of each tissue barrier. Th17 cells are relevant mediators in mucosal defense against extracellular bacteria and fungi. Yet, their role in shaping human microbial communities at the oral barrier was not well-understood. To appreciate how Th17 immunity affects the oral microbiome establishment, we performed studies in a patient cohort with Autosomal-Dominant Hyper IgE Syndrome (AD-HIES) that exhibits impaired Th17 differentiation due to loss-of-function mutations in the transcription factor STAT3. We confirmed that AD-HIES patients display a significant susceptibility to oral fungal infections. Our characterization of their mycobiome during active candidiasis revealed a dominance of Candida albicans, alongside a generalized depletion of health-associated bacteria with the exception of Streptococcus, which were overrepresented. These results demonstrate the critical role of Th17 immunity in the containment of C. albicans as a commensal and suggest a synergistic relationship of C. albicans with streptococci, that may influence oral disease susceptibility. Finally, to understand the effects of excessive Th-17/IL-17 inflammatory responses on oral microbial communities, we evaluated patients with Leukocyte Adhesion Deficiency type-I (LAD-I), that present with severe periodontitis driven by IL-17 mediated immunopathology. Our findings revealed that exaggerated IL-17 responses are linked to dysbiosis of subgingival communities. Additionally, IL-23/IL-17 blockade treatment of an LAD-I patient demonstrated reversal of microbial shifts with immune-modulation, suggesting a causative role for IL-17 responses in LAD-associated microbial dysbiosis. In sum, our studies reveal critical roles for the IL-17/Th17 responses in establishment of the oral bacteriome/mycobiome in health and disease.
    • Impaired Histatin-5 Levels and Salivary Antimicrobial Activity against C. albicans in HIV Infected Individuals

      Al Thunayyan, Awdah Anwar; Jabra-Rizk, Mary Ann (2013)
      HIV-infected individuals constitute a population highly susceptible to opportunistic infections particularly oral candidiasis (OC) caused by the most pathogenic human fungal species Candida albicans. The susceptibility to OC is enhanced under reduced CD4+ T-cells however local host defenses may also play a key role. Host-produced salivary antimicrobial peptides are considered to be an important part of the host innate immune system involved in protection of the oral cavity against colonization and infection by microbial species. Histatin-5 (Hst-5) specifically has exhibited potent anti-candidal properties in vitro. However, its importance in protecting the oral mucosa against candidal colonization and importantly, its contribution to the observed enhanced susceptibility of HIV+ individuals to candidiasis has not been previously investigated most likely due to the lack of feasible and sensitive methods for measuring salivary Hst-5 concentrations. To that end, the goal of this study was to develop a novel immunoassay to accurately measure and analyze salivary Hst-5 levels within the context of HIV infection and oral candidal colonization in order to validate the hypothesis that salivary Hst-5 levels are compromised in HIV+ individuals. The results from these studies demonstrated that salivary Hst-5 levels are significantly (60%) decreased in HIV+ individuals compared to healthy subjects concomitant with enhanced candidal prevalence. The findings generated from this project provided new insights into oral innate immune defense mechanisms and the enhanced susceptibility of HIV+ individuals to oral candidiasis.