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Copper as a nutrient for Candida albicans at the host-pathogen interface

铜作为宿主-病原体界面白色念珠菌的营养物质

基本信息

批准号：
8956111
负责人：
Valeria C Culotta
金额：
$ 46.74万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8956111
关键词：
Active Sites Address Animals Antioxidants Binding Binding Proteins Biology Candida albicans Charge Communicable Diseases Copper Cu-Superoxide Dismutase Disseminated candidiasis Dose Elements Environment Enzymes Eukaryota Event Exposure to Face Family Fluorescence Microscopy Fluorescent Probes Half-Life Homeostasis Human Immune response Immunity Immunohistochemistry Infection Infectious Diseases Research Integration Host Factors Invaded Ions Kidney Lesion Leukocyte L1 Antigen Complex Light Manganese Superoxide Dismutase Maps Mediator of activation protein Metabolism Metals Microbe Microbial Biofilms Micronutrients Modeling Monitor Motion Mus Nutrient Nutritional Organ Organism Oxidative Stress Pathogenesis Pathway interactions Process Property Proteins Public Health Publications Reactive Oxygen Species Reading Recombinants Research Research Proposals Resolution Respiratory Burst Roentgen Rays Role Site Starvation Structure Superoxide Dismutase Surface System Testing Toxic effect Virulence Yeasts Zinc deficiency antimicrobial assault base biological adaptation to stress combat deprivation extracellular fungus in vivo insight kidney infection macrophage member mouse model mutant neutrophil novel pathogen public health relevance response trafficking

项目摘要

DESCRIPTION (provided by applicant): Copper is a highly reactive element and based on its potential toxicity, animals use the deleterious properties of Cu in anti-microbial weaponry during infectious disease. Both bacterial and fungal pathogens are attacked with toxic doses of Cu inside the animal host. However, Cu is also an essential nutrient that microbes must acquire from the host. Currently, little is understood regarding host-pathogen competitions for Cu as a nutrient. To shed light into the biology of Cu during infectious disease, this research proposal focuses on Candida albicans, the most prevalent of human fungal pathogens. C. albicans requires Cu to maintain activity of a family of extracellular superoxide dismutase (SOD) enzymes that protect the yeast from the host oxidative burst and are important for virulence. Our findings show these Cu-SODs are unprecedented in structure and function in that they lack a Zn co-factor and contain a highly irregular open Cu site that may easily capture Cu from the host. We find the intracellular Cu-SOD of C. albicans is also remarkable in that this enzyme is replaced with a non-Cu alternative (Mn-SOD3) when the yeast is starved for Cu. This swapping of SOD enzymes is part of a large adaptation to Cu starvation, and surprisingly this Cu stress response becomes evident during C. albicans invasion of the kidney in vivo. To our knowledge this is the first documented evidence for host limitation of Cu during infection. We hypothesize that the host not only attacks pathogens with elevated Cu, but can also withhold this nutrient from invading microbes and C. albicans can adapt to both. Here we shall use the family of Cu SODs in C. albicans as a read-out for fungal Cu utilization during two extremes of host Cu availability, namely the high Cu of macrophages and the low Cu of kidney infection. The extracellular Cu-SODs become particularly important during fungal encounters with the oxidative burst of macrophages and we propose that C. albicans efficiently utilizes macrophage Cu to charge its SODs for an anti-oxidant defense. In Aim 1 (To define the metal binding properties and function of diverse SOD5-like proteins in C. albicans) we address the Cu binding capacities of the extracellular SODs as predictive indicators of how well these enzymes can maintain activity at the host-pathogen interface. Additionally we will explore the function of an unknown member of the extracellular SOD family, namely SOD6, as a potentially new Cu- requiring entity for fungal pathogenesis. In Aim 2 (To understand C. albicans utilization of host copper as a nutrient during macrophage infection), we examine activation of the extracellular fungal SODs in a macrophage infection model and define the pathway by which macrophage Cu is ultimately delivered to the active site of the fungal SOD enzymes. Lastly, Aim 3 (To understand the fungal Cu starvation response at the host-pathogen interface) will explore the kidney model of infection and define the mechanism whereby the host withholds Cu from C. albicans as the first documented nutritional immunity response involving Cu. Collectively, these studies promise to provide new insight into the implications for Cu as a nutrient for fungal pathogenesis.