C. albicans invasive growth promotes oropharyngeal infections

白色念珠菌侵入性生长促进口咽部感染

基本信息

批准号：
9014539
负责人：
James B Konopka
金额：
$ 23.7万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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：
2015-02-15 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014539
关键词：
AIDS-Related Opportunistic Infections Acquired Immunodeficiency Syndrome Affect Agar Antifungal Agents Applications Grants Azole resistance Azoles Biological Assay Candida Candida albicans Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Clinical Collection Critical Pathways Data Defect Development Drug resistance Engineering Epithelial Epithelial Cells Fluconazole resistance Future Genes Goals Growth HIV Health Human Hyphae Immunocompromised Host In Vitro Individual Infection Invaded Lead Libraries Methods Modeling Molecular Monitor Morbidity - disease rate Morphology Mucous Membrane Multi-Drug Resistance Mus Mutate Oral cavity Organism Oropharyngeal Orthologous Gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Process Proteins Reporting Resistance Role Saccharomyces cerevisiae Series Serum Signal Transduction Skin Testing Thinking Tissues cellular engineering design effective therapy human disease in vitro Assay insight mouse model mutant new therapeutic target novel novel therapeutic intervention oral infection oropharyngeal thrush pathogen prevent resistant strain screening

项目摘要

DESCRIPTION (provided by applicant): Candida albicans is an opportunistic fungal pathogen that causes oropharyngeal infections in immunocompromised patients, including those with AIDS. It is usually one of the first clinical signs to appear as HIV-infected individuals progress o AIDS, and leads to serious morbidity if untreated. The azole class of antifungal drugs is currently used to prevent and treat oropharyngeal candidiasis. However, the emergence of drug resistant strains now makes it critical to develop new therapeutic strategies for oropharyngeal candidiasis. A key step in establishing C. albicans infections is the ability of this organism to grow invasively into epithelial tissues. To better define the mechanisms of C. albicans pathogenesis, studies are proposed to identify genes needed for invasive growth of C. albicans. This process has not been assessed systematically in previous studies of oropharyngeal candidiasis. Therefore, collections of C. albicans deletion mutants that have become available were screened to identify a broad set of genes needed for invasive growth into agar medium in vitro. Screening conditions were optimized to identify strongly defective mutants. The first goal will be to determine which of the mutants are defective in invading epithelial cells in vitro. Mutants with strong defects will then be examined for ability to undergo invasive hyphal growth into engineered mucosal cell layers. Those mutants observed to have significant defects in vitro will then be tested for ability to cause oropharyngeal candidiasis in mice, which serves as a good model for the human disease. These studies will reveal novel mechanisms involved in invasive growth, since about half of the mutants affect genes that have not been studied in any detail previously. The results are expected to identify new pathways that are critical for C. albicans to undergo invasive growth and cause oropharyngeal candidiasis in AIDS patients. These pathways will be targeted in future studies to develop novel therapeutic approaches.

描述（由申请人提供）：白色念珠菌是一种机会性真菌病原体，可引起免疫功能低下患者（包括艾滋病患者）口咽部感染。它通常是 HIV 感染者进展为艾滋病时出现的第一个临床症状之一，并导致艾滋病。如果不治疗则发病严重。目前使用唑类抗真菌药物来预防和治疗口咽念珠菌病。耐药菌株现在使得开发口咽念珠菌病的新治疗策略变得至关重要，建立白色念珠菌感染的关键步骤是该微生物侵入性生长到上皮组织中的能力。为了更好地确定白色念珠菌的发病机制。提议鉴定白色念珠菌侵入性生长所需的基因，这一过程在之前的口咽念珠菌病研究中尚未得到系统评估。对现有的白色念珠菌缺失突变体进行筛选，以确定在体外侵入性生长到琼脂培养基中所需的一系列基因。优化筛选条件，以识别强烈缺陷的突变体。然后，将检查具有强烈缺陷的突变体在体外侵入性菌丝生长到工程化粘膜细胞层中的能力，然后将测试那些在体外观察到具有显着缺陷的突变体。能够在小鼠中引起口咽念珠菌病，这是人类疾病的良好模型。这些研究将揭示涉及侵入性生长的新机制，因为预计大约有一半的突变体会影响以前未详细研究过的基因。以确定对白色念珠菌侵袭性生长和导致艾滋病患者口咽念珠菌病至关重要的新途径，这些途径将成为未来研究的目标，以开发新的治疗方法。