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Inhibition of Candida virulence and biofilm formation by a bacterial peptide

细菌肽抑制念珠菌毒力和生物膜形成

基本信息

批准号：
10621569
负责人：
Danielle A Garsin
金额：
$ 7.6万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621569
关键词：
Acquired Immunodeficiency Syndrome Actins Adherence Adhesions Affect Amino Acids Animal Model Antibiotics Antifungal Agents Area Attenuated Bacteria Bacterial Adhesins Binding Biochemical Biogenesis Biological Biology Caenorhabditis elegans Candida Candida albicans Candidiasis Cell Surface Proteins Cell Wall Cell surface Cells Chemicals Data Development Disease model Enterococcus faecalis Epithelial Epithelial Cells Felis catus Generations Genes Genetic Glycoproteins Goals Growth HIV Seropositivity Head and neck structure Homologous Gene Human Microbiome Immunocompromised Host In Vitro Infant Infection Inflammation Investigation Knowledge Label Malignant Neoplasms Medical Membrane Microdomains Microbial Biofilms Modeling Morbidity - disease rate Morphogenesis Mus Oral Oral candidiasis Oral cavity Outcome Pathway interactions Patients Peptide Hydrolases Peptides Post-Translational Protein Processing Process Proteins Public Health Radiation Research Risk Role Signal Pathway Site Source Steroids Surface Testing Therapeutic Vertebrates Virulence Work Yeasts base cell envelope cell growth chemotherapy design disulfide bond efficacy testing experimental study fungus gastrointestinal gene product genetic approach gut colonization immunosuppressed innovation macrophage microorganism interaction mouse model mutant nanomolar normal microbiota novel novel strategies novel therapeutics oral cavity epithelium oral infection oropharyngeal thrush prevent therapeutic development tissue/cell culture treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT The medical condition oropharyngeal candidiasis (OPC) is a major source of oral morbidity in patient groups including the immunosuppressed (cancer and AIDS patients) and those taking broad-spectrum antibiotics. We recently identified a peptide produced by Enterococcus faecalis that inhibits the hyphal morphogenesis and biofilm formation of the primary causative agent of OPC, Candida albicans. The research proposed in this ap- plication seeks to understand how the mature form of this peptide, EntV, is generated, how it targets C. albi- cans hyphal morphogenesis, and the extent to which it protects against OPC, thereby filling a critical gap in our knowledge and providing new avenues for the development of therapeutics. The long-term goal of this re- search is to develop novel strategies for treating and preventing oropharyngeal candidiasis. The objective of this application is to determine the generation, mode of action and therapeutic potential of EntV. The central hypothesis is that secreted and processed EntV acts on signaling pathway(s) that controls hyphal development in C. albicans resulting in protection from candidiasis. The rationale for this research is that identification of the mechanism by which EntV inhibits the formation of the invasive form of C. albicans will lead to new treatment strategies. By pursing three aims, the objective of this application will be attained. Aim #1 will elucidate how the active form of EntV is generated. Using both genetic and biochemical approaches, we will test the hypothesis that the proteases GelE and/or SprE are required for cleavage, and disulfide bond formation is catalyzed by a DsbA homolog. In Aim #2, the genes/pathways of C. albicans that are targeted by E. faecalis to inhibit hyphal morphogenesis will be determined using cell biological and genetic approaches. Based on preliminary data, the working hypothesis is that EntV interacts directly with one of several known discrete subdomains on the C. albicans cell surface to disrupt cell-cell and cell-substrate adherence, both of which are essential for biofilm formation. The efficacy of EntV and related peptides in protecting against C. albicans infection will be tested in Aim #3. Tissue culture cells (macrophages and oral epithelial cells) and mouse models of OPC and gastroin- testinal colonization will be utilized. We postulate that EntV will protect against C. albicans infection and can- didiasis in the nanomolar range. The significance of this contribution will be the knowledge of how a bacterial peptide inhibits C. albicans hyphal morphogenesis, potentially opening new avenues for therapeutic design. Targeting hyphal morphogenesis as an area for the possible development of novel therapeutics is innovative, as current antifungals are directed against the integrity or growth of the cell envelope. Additional benefits of this research include new knowledge in the fields of bacterial peptide generation, fungal morphotype switching, and inter-kingdom microbial interactions.

项目总结/文摘