Immunosuppression is associated with many diseases caused by organisms that are normally non- pathogenic. Oropharyngeal candidiasis (OPC), caused by the yeast Candida albicans, is a major disease associated with immunosuppression due to chemotherapy, AIDS or congenital immunodeficiency. The defense mechanisms that limit oral Candida in normal individuals cover the spectrum of innate and acquired immunity. Of late, much emphasis has been on CD4+ T cells due to the strikingly high incidence of OPC in HIV+ individuals. However, innate immune mechanisms such as neutrophils and anti-microbial proteins also exert important anti-fungal activities. Although innate effectors such as neutrophils and 2-defensins are classically thought to operate primarily before acquired immunity begins, a new paradigm has emerged suggesting that a new population of CD4+ T cells termed """"""""Th17"""""""" can drive innate immunity and provide essential host defense mechanisms to fungi. T cell-dependent host responses have traditionally been classified into """"""""Th1"""""""" or """"""""Th2"""""""" depending on the cytokines produced by each subset (IFN3 and IL-4, respectively). However, a major revision in the Th1/Th2 paradigm occurred in the last two years, leading to the recognition of an IL-17-secreting CD4+ T cell subset that arises independently from the classic Th1 and Th2 lineages. Th17 cells are characterized by secretion of IL-17, IL-17F and IL-22, and are driven to develop by TGF2+IL-6+IL-23 rather than by IL- 12 (Th1 cells) or IL-4 (Th2 cells). Although made by T cells, IL-17 plays a non-redundant and essential role in controlling innate immunity. Specifically, IL-17 controls neutrophil function in vivo, and also regulates expression of anti-microbial molecules involved in anti-fungal immunity, particularly 2- defensins. Consequently, IL-17-deficient mice are highly susceptible to a variety of infectious diseases, including disseminated candidiasis. Although less well characterized, IL-17F and IL-22 appear to have similar functions. Accordingly, we hypothesize that Th17 cells and their major cytokines (IL-17, IL- 17F and IL-22) play non-redundant roles in host defense against OPC, and that Th17 cells rather than Th1 cells are the dominant host-defensive mechanism. This hypothesis will be tested in using a mouse model of OPC with mice deficient in IL-17 receptor signaling (IL-17RAKO and IL-17RCKO mice, Aim 1), mice deficient in IL-22 signaling (IL-22KO mice Aim 2) or mice deficient in either Th1 or Th17 development (via IL-12p35KO or IL-23p19KO mice, Aim 3). Collectively, these experiments will shed new light on immune mechanisms required to limit OPC, which could ultimately point the way to new therapies for this disease.
Oral candidiasis, also known as oral thrush, is an AIDS-defining fungal infection of the oral cavity that can affect up to 90% of HIV+ individuals. This disease is also problematic in other classes of immunosuppressed patients, such as infants, the elderly, or cancer patients undergoing chemotherapy. The objective of this project is to understand in detail how the immune system normally keeps oral candidiasis under control, in order to develop better therapies and to understand the consequences of therapies that suppress specific immune events. ? ? ?
