Research Focus

What causes the fuzzy white patches commonly found on the tongues of babies? These patches are a fungal infection, commonly referred to as thrush, caused by the commensal fungus Candida albicans (C. albicans). We investigate the role of the oral mucosa and salivary gland in antifungal immunity to this opportunistic pathogen. Since C. albicans is a normal part of the oral flora it rarely causes disease, but can become pathogenic when the immune system is compromised. In addition to oral candidiasis (oropharyngeal or OPC), C. albicans causes different diseases including dermal, vaginal and disseminated candidiasis. OPC is common in infants, the elderly, denture wearers, patients on antibiotic treatments and those with various salivary defects. OPC is a serious complication for immunocompromised populations, including Sjögren’s Syndrome patients, cancer patients undergoing chemotherapy or head-neck irradiation, as well as individuals with HIV/AIDS. The other forms of candidiasis (vaginal, dermal and disseminated) are rarely diagnosed in HIV/AIDS+ or other immunodeficient patients. Thus, CD4+ T cells appear to play a dominant role in protecting against oral Candida infection, but not other forms of the disease. Individuals with rare genetic defects such as Hyper-IgE (HIES, Job’s) Syndrome have elucidated the crucial role of CD4+ Th17-associated cytokines IL-23 and IL-17 in protection to OPC. IL-17 upregulates neutrophil chemokines, antimicrobial proteins (AMPs) and pro-inflammatory cytokines such as IL-6. IL-17 binds to the IL-17R, composed of subunits IL-17RA and IL-17RC, which are highly expressed on epithelial and stromal cells, including oral tissue. We showed that both IL-17RA and IL-17RC are essential for immunity to OPC. While it is clear that the IL-17 signaling axis is vital for defense against OPC, the underlying mechanisms that provide immunity at the mucosal surface are not well defined

Immune Cells in the Oral Mucosa

We were the first group to link IL-17 and oral mucosal immunity, both in the context of OPC and periodontal disease. In addition to CD4+ Th17 cells, protection to OPC requires a potent innate response, mediated in part directly by the oral mucosa. The oral mucosal surface is unique as it facilitates the first interactions at the beginning of the GI tract between foreign pathogens, commensal microbiota and the host immune system. To date, the implications of these interactions in disease and immune homeostasis have been understudied in the oral cavity. The innate cells involved in protection to OPC are not well understood. We have recently defined ‘natural’ (n) Th17 cells as an important innate source of IL-17 during acute OPC. We will further investigate how these and other innate immune cells are regulated in the oral mucosa during Candida infection using techniques such as flow cytometry. Other projects include investigating the role of different AMPs in protection against candidiasis.

Salivary Components Involved in Antifungal Immunity

Saliva is often an underappreciated part of the immune response in the oral cavity. Saliva is an important immune component though, as patients with salivary defects are highly susceptible to OPC. We demonstrated that mouse and human salivary components, defensins and histatins, are essential in limiting Candida carriage and infection. Protection to OPC involves components derived from oral epithelium and salivary gland, but the underlying mechanisms of IL-17 anti-Candida host defense are largely undefined. We have projects aimed at investigating the specific role of IL-17 in the oral epithelium and the salivary gland using conditional knockout mouse systems.

Damage to the Oral Mucosa

The most common complications of non-surgical treatments for oral cancers are mucositis and xerostomia. All patients receiving targeted head-neck radiotherapy develop mucosal damage, known as oral mucositis (OM). The importance of an intact mucosal layer in defense against OPC is demonstrated by the high susceptibility of patients with OM to Candida infection. We investigate these processes using a mouse model of disease in order to examine the consequences of barrier destruction, the role of IL-17 in maintaining mucosal integrity and how OPC progresses during the stages of OM. We hope to make discoveries that lead to the development of improved therapeutics that promote oral health.