The role of platelets in modulation of the immune response is not completely understood. The goal of this project is to investigate the immunomodulatory role of platelets in oropharyngeal candidiasis (OPC) caused by Candida albicans. Normally considered for their role in clotting, platelets are also important for protection against bacterial infection, via various mechanisms including regulation of neutrophil function. Platelets interact with Candida, yet the consequences of this interaction during OPC are unknown. The long-term goal is to understand the role of platelets in mucosal and disseminated fungal infection. This is a critical relationship to understand since fungal infections are a major complication for the immunocompromised including cancer and HIV+ patients. The overall objective of this application is to determine how platelets regulate the immune response during OPC. The central hypothesis is that platelets are required for effective protection against OPC. This hypothesis is based in part on preliminary data produced in the PI's laboratory. The rationale that underlies the proposed study is that once it is known how platelets regulate oral mucosal immunity, therapeutics involving platelets can be developed to effectively treat Candida infections. This hypothesis will be tested in the following three specific aims: 1) Assess the role of platelets in oral clearance of C. albicans; 2) Determine the mechanism(s) of dissemination of C. albicans after OPC; and 3) Identify how platelet deficiency affects IL-17-mediated immunity to OPC. Collaborators have developed a mouse strain in which platelet depletion can be induced and maintained for several weeks.
In Aim 1, platelet-depleted mice will be subjected to a well-established model of acute OPC to determine susceptibility. Preliminary data indicate susceptibility of platelet-depleted mice to OPC, with an associated decrease in a protective neutrophil influx into the mucosa. How platelets influence neutrophil recruitment, activation and/or neutrophil extracellular trap formation will be determined. Preliminary data indicate that in the absence of platelets Candida disseminates to the kidney during OPC.
In Aim 2, mice will be infected to determine how platelets prevent fungus from breeching the mucosal barrier, and if Candida is detected in the blood how platelets contribute to clearance.
In Aim 3, flow cytometry will be employed to determine the cell populations regulated by platelets during OPC. IL-17, produced by innate lymphocytes including ??-T cells, is necessary for protection against acute OPC, via downstream regulation of neutrophils and defensins. How platelets intersect with the IL-17-pathway is unknown. Platelets regulate ??-T cells cells in other systems including melanoma, and preliminary data show that Il17 transcript and ??-T cells in tongue are significantly reduced in platelet-depleted mice compared to wild type. The approach of this study is innovative, because it shifts the focus to the immune regulatory capacity of platelets. The proposed research is significant, since with a more complete knowledge of the mediators regulating the inflammatory response, better therapeutics can be developed to clear Candida infections.
The oral epithelium is important in host protection against oral fungal infections caused by the commensal fungus Candida albicans, but the immune mediators and cell populations involved are not well understood. The proposed research is relevant to public health because Candida albicans can cause serious infections in patients with immune system defects. This proposal will study the role of platelets and innate immune cells in protection against disease caused by Candida albicans.
