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Genetic and mechanistic analysis of carbon dioxide tolerance in Cryptococcus pathogenesis

隐球菌发病机制中二氧化碳耐受性的遗传和机制分析

基本信息

批准号：
10548836
负责人：
Damian J Krysan
金额：
$ 63.08万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-18 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548836
关键词：
Affect Air Anabolism Biological Carbon Carbon Dioxide Cessation of life Clinical Cryptococcal Meningitis Cryptococcus Cryptococcus neoformans DNA Sequence Alteration Data Disease Drug Targeting Environment Event Evolution Future Gene Expression Profile Genes Genetic Genetic Polymorphism Genetic Screening Genetic Transcription Genomic approach Genomics Genotype Glycolysis Goals Growth HIV antiretroviral HIV diagnosis HIV therapy HIV/AIDS High temperature of physical object Homeostasis Human In Vitro Incidence Infection Lung Maps Meningoencephalitis Metabolism Minority Modeling Molecular Molecular Target Mus Mutation Opportunistic Infections Outcome Pathogenesis Pathway interactions Patients Persons Phenotype Positioning Attribute Property Publishing Quantitative Trait Loci Resource-limited setting Role Sentinel Sphingolipids Symptoms Testing Tumor Biology Variant Virulence Virulent Yeasts antiretroviral therapy burden of illness capsule deletion library design differential expression experience experimental study fitness genetic resource genome wide association study improved inhibitor mortality mouse model mutant new therapeutic target novel anticancer drug novel therapeutics pathogenic fungus patient population response trait transmission process

项目摘要

Abstract Cryptococcal meningoencephalitis (CME) is one of the most important opportunistic infections affecting people with HIV/AIDS. The importance of this disease is due not only to its high incidence and mortality in this and other patient populations but also to the fact that symptoms of CME are a common sentinel event leading to the diagnosis of HIV/AIDS. Thus, many patients must first survive CME before they can benefit from the advances in HIV therapy. Unfortunately, the outcomes for CME therapy are far from acceptable, particularly in resource-limited regions with high burdens of disease. Consequently, effective and widely available therapies for CME are an unmet clinical need of global importance. Cryptococcus spp. are basidiomycetous yeasts whose primary niche is the external environment. As such, only strains and species of Cryptococcus that can transition to, and replicate within, the human host are able to cause disease. Our central premise is that an understanding of the biological mechanisms required for Cryptococcus to survive in human beings could provide new targets for therapy in the same way as studying tumor biology informs the design of new anti- cancer drugs. An important environmental distinction between the human host and the natural niche of Cryptococcus is the concentration of carbon dioxide (CO2). We hypothesized that adaptation to host levels of CO2 may represent a critical step in Cryptococcus pathogenesis. To specifically test this hypothesis, we compared the growth of C. neoformans var. grubii strains under conditions that varied only in the concentration of CO2. Consistent with our hypothesis, the growth rate was reduced at concentrations of CO2 experienced in the host. Next, we tested the CO2 tolerance of a set of environmental strains with known virulence properties in a mouse model; strains with reduced growth in the presence of host concentrations of CO2 were avirulent while those with growth rates that matched clinical isolates from human patients were virulent. We, therefore, have discovered that CO2 tolerance is a previously unrecognized host environment-associated virulence attribute of C. neoformans. Accordingly, the goal of this proposal is to identify the genetic, transcriptional, and regulatory responses that allow specific strains of C. neoformans to respond to host concentrations of CO2 and, thereby, cause CME. To accomplish these goals, we propose the following specific aims: Aim 1. Characterize the virulence, transcriptional, and genomic distinctions between CO2- tolerant and -non-tolerant C. neoformans strains; Aim 2. Identify genes required for CO2 tolerance through targeted and large-scale genetic screening; and Aim 3. Determine the molecular mechanisms of genes required for C. neoformans CO2 response. Successful execution of these aims will not only further our understanding C. neoformans pathogenesis and host survival but also identify new molecular targets for future exploration as drug targets.

摘要