AIDS and Immunosuppression Program, Integrative Biology and Infectious Diseases Branch, DER, NIDCR
This concept will encourage basic and translational research projects aiming to understand the role of and the mechanism by which the oral microbiota influences oral HIV pathogenesis, mucosal immunity, immune cell homeostasis, and the immunogenicity and efficacy of prophylactic HIV vaccines. Findings from this research will inform the development of new prevention and therapeutic strategies to modulate the oral microbiota with the goal of understanding the physiological processes indicated above.
The oral microbiota is distinct in its composition of a unique community of microorganisms comprising predominantly 200 bacterial species, harboring approximately 50-100 billion bacteria. The oral microbiota contains about 700 taxa of which only less than one-third have not been grown in vitro. This oral microbial ecosystem also contains archaeal, eukaryotic and viral species. The oral microbiota represents a compartment of the gastrointestinal microbiota, in which the total number of resident microbes occurs at approximately the same number of cells in the human body. The gastrointestinal microbiota is dominated by four major phyla, which in order of abundance are: Firmicutes, Bacteroidetes, Actinobacter and Proteobacter. The richness of the gastrointestinal microbiota creates the potential for infinite variation in microbial composition among humans, giving rise to a dynamic microbial signature for each individual.
There is an increasing recognition that the human microbiota is an integral part of the body, playing a central role in regulating human health. A healthy oral microbial ecosystem embodies a stable and nutrient-rich environment that supports homeostasis and actively participates in the maintenance of the entire gastrointestinal health. The oral microbiota composition is constantly fine-tuned and shaped by the regulatory function of the individual’s immune system. The latter is also concomitantly refined by colonizing oral microbial species, generating a biologically-critical, symbiotic relationship that maintains an active oral health status. For instance, the microbiota interacts with the host to modulate the immune system for self-recognition, facilitates digestion and the production of energy metabolites needed for central metabolic functions, produces signaling molecules used in microbiota-host interactions, enables drug metabolism, and facilitates the production of vitamins and antimicrobial peptides.
While oral microbial ecosystems are stable, perturbations of the oral microbiota and oral dysbiosis have been reported and they have been partially linked to immune dysfunction and exacerbation of HIV/AIDS disease status. Despite understanding the importance and role of the oral ecosystem in oral health and disease, limited information is known regarding how the oral microbiota and its changes impact oral HIV pathogenesis, mucosal immunity, acute and chronic infection, viremia, transmission, latency, effectiveness of therapy, and immunogenicity and efficacy of oral prophylactic HIV vaccines. It is also not known how initial HIV/AIDS infection exerts an impact on the homeostasis of normal oral microbiota. Changes in oral HIV pathogenesis and immunity driven by alterations in the oral microbiota may lead to enhanced acquisition, replication, and latency with unknown but potential systemic dissemination. In contrast to the knowledge gap described above for the oral microbiota and HIV/AIDS in the oral mucosa, more information is known regarding the gut microbiota and HIV pathogenesis, immunity, immune cell homeostasis, and the immunogenicity of HIV vaccines.
This concept represents a unique opportunity that takes advantage of the existing intellectual and technological resources to address the scientific gaps described above. Specifically, the NIH Human Microbiota Project (HMP; 2007-2015) created a platform to characterize the human microbiota composition at multiple anatomical compartments of the body, including the oral mucosa, to establish its role in health and disease. This effort has catalyzed novel technologies and coalesced a cadre of investigators who can be tapped into to address the role of the oral microbiota in HIV pathogenesis, immunity, and the efficacy of prophylactic HIV vaccines in the oral mucosa. Obtaining knowledge about the functional impact of the oral microbiota on HIV/AIDS-associated oral diseases is critical and will be of high impact to public health as it will inform the development of new prevention and therapeutic interventions to control the processes described above.
Examples of research topics supported by this initiative include but are not limited to:
- Define oral microbiota perturbations that exacerbate oral HIV pathogenesis and associated oral diseases
- Define how HIV infection may disrupt the composition of normal oral microbiota
- Delineate mechanisms for oral microbiota-host’s immune system interactions that maintain homeostasis, or that trigger immune dysfunction and oral diseases
- Determine the mechanisms that govern the adjuvant effect of the oral microbiota in oral HIV vaccine-induce immune responses
- Define the mechanisms by which the oral microbiota interferes with oral prophylactic HIV vaccine immunogenicity and efficacy in non-human primate models
- Define mechanisms by which maternal vaginal microbiota in HIV-infected mothers exert an impact on offspring’s oral microbiota and HIV-associated oral diseases
Current Portfolio Overview
The NIDCR has been part of the HMP and it has pioneered oral microbiota studies, defining the unique composition of the oral microbiota. The NIDCR through its AIDS and Immunosuppression Program (AIP) has seeded oral microbiota studies associated with HIV/AIDS in FY2010 with the RFA-DE-10-003, which resulted in three grants awarded and eight papers published. Currently, the portfolio has three active grants. Investigators are addressing the impact of the oral microbiota on: growth of HIV exposed, but uninfected infants; HIV-associated oral warts and Candidiasis; and cancer chemotherapy and oral mucositis. As described above in this concept, the portfolio has multiple research gaps not addressed by the active grants. After the initial descriptive studies that defined the standard oral microbiota composition in healthy status, it is imperative to determine the functional impact of the oral microbiota in disease status such as HIV/AIDS as outlined in this concept.
Alignment with Institute Goals, Strategies and Implementation Plan
This initiative is aligned with the NIDCR’s Strategic Plan 2014-2019, Goal I, Objective 1 (enable basic research to advance knowledge of dental, oral, and craniofacial health) and with the FY2016 Trans-NIH Plan for HIV-Related Research on vaccine development.
- The Fungal Biome of the Oral Cavity. Chandra J1, Retuerto M, Mukherjee PK, Ghannoum M. Methods Mol Biol. 2016; 1356: 107-35.
- The oral microbiota in human immunodeficiency virus (HIV)-positive individuals. Kistler, J.O., Arirachakaran, P., Poovorawan, Y., Dahlén, G., and Wade, W.G. J Med Microbiol. 2015 Sep; 64(9): 1094-101.
- The Oral Bacterial Communities of Children with Well-Controlled HIV Infection and without HIV Infection. Goldberg, B.E., Mongodin, E.F., Jones, C.E., Chung, M., Fraser, C.M., Tate, A., and Zeichner, S.L. PLoS One. 2015 Jul 6; 10(7): e0131615.
- Quorum-sensing dysbiotic shifts in the HIV-infected oral metabiome. Brown, R.E., Ghannoum, M.A., Mukherjee, P.K., Gillevet, P.M., and Sikaroodi, M. PLoS One. 2015 Apr 17; 10(4): e0123880.
- HIV infection and microbial diversity in saliva. Li, Y., Saxena, D., Chen, Z., Liu, G., Abrams, W.R., Phelan, J.A., Norman, R.G., Fisch, G.S., Corby, P.M., Dewhirst, F., Paster, B.J., Kokaras, A.S., and Malamud, D. J Clin Microbiol. 2014 May; 52(5): 1400-11 .