Monday, April 21, 2025
4/21/2025
Candidalysin: a key mediator of Candida vaginitis immunopathology - Candida albicans, the primary causative agent of fungal vaginitis, will affect 75% of all women of reproductive age at least once in their lifetime. Long believed to result from immunodeficiency, a growing body of evidence strongly suggests that vaginitis is now considered to be an immunopathology, in which the host response actually drives disease symptoms. Lack of a comprehensive understanding of the host and fungal factors that initiate symptomatic disease remains a significant barrier to progress in better treating and managing this most prevalent human fungal infection. Guided by strong published and preliminary data, we have identified that the fungal peptide toxin candidalysin is the major virulence determinant driving vaginitis pathogenesis and that amino acid variation of this effector exists amongst C. albicans clinical isolates that impacts pathogenicity. Therefore, the objectives of this proposal are to determine the capacity to which novel candidalysin variants can drive IL-1 signaling during vaginitis and whether vaccination strategies and novel thiobenzoate chemical scaffolds can block both fungal growth and/or inflammation to better resolve disease symptoms. Under the first aim, we will determine if novel amino acid candidalysin variants observed in clinical isolates impact pathogenicity or competitive fitness in vivo. We will also determine structure-function activity of the entire candidalysin coding sequence by performing alanine scanning to identify non-toxic vaccine candidates that my limit immunopathology following immunization. The second aim will focus on delineating redundant and unique contributions of IL-1 isoforms in controlling fungal burden and driving inflammation at the vaginal mucosa and which cell types produce IL-1 during vaginal infection. We will use a series of constitutive and conditional knockouts to further probe which cell types respond to and govern IL-1-dependent phenotypes. The third aim seeks to validate previously and newly identified small molecules that possess both anti-inflammatory and antifungal activity using an established pipeline from in silico molecular docking to functional validation. The outcomes of this project will provide foundational information regarding function of novel candidalysin isoform variants, candidalysin-dependent IL-1 responses during vaginitis, and identify promising new chemical scaffolds to impede IL-1 signaling that may be exploited for improved clinical management of vaginitis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).