Immunology and Immunotherapy Program
Center for Infectious Diseases and Immunology
OBJECTIVE:
This Initiative aims to stimulate research that will address, at a molecular and cellular level, ontogeny (i.e., the age-related development) of recognition of and response to oral microbes by the innate immune system. Specifically, the Initiative will solicit research that will define how the host, beginning at birth, distinguishes between commensal (normal flora) and pathogenic microbes. Investigators will be asked to study the molecules on oral microbes recognized by the innate immune system. They will also be asked to determine how the host recognizes the molecules on the microbes, and how the host recognition changes with age. Moreover, research will be solicited on the ontogeny of salivary and epithelial components related to innate immunity. Finally, this Initiative seeks research on the ontogeny of molecular mechanisms by which the innate immune system responds to oral microbes, the possible individual host genetic differences in innate immunity to oral microbes, and the connection between host innate and adaptive immune systems.
The research is expected to provide a fundamental understanding of how the host usually tolerates the presence of over 700 species of microbes in the oral cavity without adverse effects. Also, this research will provide information about how the host innate immune system protects the body from pathogenic microbes. This Initiative might lead to new approaches for immunomodulation and the design of highly specific antimicrobial agents.
BACKGROUND:
Most of the bacteria, viruses, fungi and parasites that constitute the oral microflora are commensals, coexisting within the oral cavity without causing disease. Such harmonious interplay is due to a dynamic molecular cross-talk between the microflora and the host, and the capacity of the innate immune system to recognize most of the microbes as non-harmful. How the innate immune system, an evolutionarily ancient response, accomplishes this is unknown. The molecular basis for host-commensal mutualism is one of the fundamental questions in contemporary immunology, and related to, and as important as, the quest for an explanation of how the host distinguishes self from nonself.
The mucosa and saliva in the oral cavity contributes to innate immunity. The oral mucosa is a moist layer of semi-permeable tissue lining the mouth, and includes epithelial cells, fibroblasts, neutrophils, macrophage, lymphocytes, and dendritic cells. The mucosa provides a barrier to microbial invasion through physical interference, phagocytosis, secretion of defensins, cytokines, chemokines, and proteases, and selective exudation of serum components. Saliva provides protection by constantly flushing non-adhered microbes, their toxins and nutrients out of the mouth. Saliva also contains a wide spectrum of antimicrobial agents such as lactoferrin, lysozyme, histatins, cystatins, mucins, agglutinins, secretory leukocyte proteinase inhibitor, tissue inhibitors of proteinases, chitinase, peroxidases, and calprotectin.
The ontogeny of innate immune discrimination of commensal and pathogenic microbes is poorly understood. Studies show that adaptive immune responses, such as the production of antigen specific immune cells and antibodies, do not appear until about one month of age and reach maturity during the second and third year of life. In contrast, the innate immune response is believed to be present and functional immediately after birth or within the first few days of life. The innate immune system, together with maternal immune factors from breast milk, appears to protect the infant from infection during early infancy.
Innate immunity was formerly thought to be a non-specific immune response characterized mainly by phagocytosis. However, recent studies show that innate immunity has considerable specificity, and is capable of discriminating between individual species of microbes. In this regard, pathogens are “seen” as dangerous to the host and elicit an inflammatory response capable of destroying the microbes, whereas commensals do not elicit such a response and their survival is tolerated by the host. This immune discrimination is achieved through the recognition of multiple microbe-specific surface molecules by pattern-recognition receptors (PRRs) present on mucosal cells. There are several types of PRRs including the nucleotide binding oligomerization domain family of proteins (Nod1, Nod2), Toll-like receptors, and the receptors for complement, glucans, and mannose. The PRR-recognized molecules on the microbes include surface proteins, nucleic acids and carbohydrates (e.g., lipopolysaccharide, peptidoglycan, lipoteichoic acids) and host factors that bind to the microbial surfaces include complement fragments and salivary components. Such “patterns” are referred to as microbe-associated molecular patterns (MAMPs) and the innate immune system is thought to recognize at least 1000 MAMPs. MAMPs include molecular patterns of commensals and pathogens (PAMPs).
PRR interactions with pathogen MAMPs trigger a complex set of intracellular signaling cascades that ultimately result in expression of antimicrobial factors as well as pro-inflammatory molecules. These responses include activation of complement, coagulation, phagocytosis, inflammation, and apoptosis. In addition, the innate immune system assists the adaptive immune system in recognition of microbial antigens and production of a robust antibody response. How PRRs react to MAMPs on commensal microbes has not been described. Dysfunction in the discrimination between oral commensal and pathogenic microbes could lead to either an ineffective immune response and infection by relatively harmless microbes, or a hyperactive immune response characterized by inflammation and host tissue destruction. The influence of age on these processes is currently unknown.
This Initiative is feasible because of the relatively easy access to oral mucosa and saliva, availability of good animal models to study oral innate immunity, and the advent of bioinformatics, genomics, proteomics, as well as new, state-of-the art technologies for tissue analyses. Existing research communities are studying innate recognition of and responses to intestinal microbes. A goal of this initiative will be to build upon knowledge gained from those studies and to encourage those as well as other investigators to elucidate the mechanisms involved in the ontogeny of oral innate immunity.
Studies of innate immunity will help the research and medical communities better understand ways to protect against oral infectious diseases, throughout individuals lifespans. This, in turn, will help patients maintain or achieve oral health in which commensal microbes survive while proliferation of pathogenic microbes is curbed.
CURRENT PORTFOLIO OVERVIEW:
Currently, NIDCR is not supporting any studies on the ontogeny of host innate immune recognition and response to oral microbes in animals or humans.
RECOMMENDATIONS FROM WORKSHOPS:
Ontogeny of host innate immune recognition of and response to oral microbes was recommended at the NIDCR Mucosal Advisory meeting held in October 2004 and at the Keystone Symposium 2005 on Innate Immunity
FUNDING MECHANISMS:
This initiative will utilize the R01 and R21 mechanisms.