C. albicans invasive growth promotes oropharyngeal infections

白色念珠菌侵入性生长促进口咽部感染

• 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
• 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

 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（由申请方提供）：白色念珠菌是一种机会性真菌病原体，可导致免疫功能低下患者（包括艾滋病患者）口咽部感染。它通常是HIV感染者进展为AIDS时最先出现的临床症状之一，如果不治疗会导致严重的发病率。唑类抗真菌药物目前用于预防和治疗口咽念珠菌病。然而，耐药菌株的出现使得开发新的口咽念珠菌病治疗策略变得至关重要。建立C.白色念珠菌感染是这种生物体侵入上皮组织生长的能力。为了更好地阐明C.白念珠菌的致病机制，研究提出了确定所需的基因的侵袭性生长的C。白色念珠菌这一过程尚未在以往的口咽念珠菌病研究中进行系统评估。因此，C.筛选已经可用的白色念珠菌缺失突变体，以鉴定体外侵入性生长到琼脂培养基中所需的一组广泛的基因。筛选条件进行了优化，以确定强烈缺陷的突变体。第一个目标是确定哪些突变体在体外入侵上皮细胞方面存在缺陷。然后将检查具有强缺陷的突变体进行侵入性菌丝生长到工程化粘膜细胞层中的能力。那些在体外观察到有明显缺陷的突变体将被测试在小鼠中引起口咽念珠菌病的能力，这是人类疾病的良好模型。这些研究将揭示与侵入性生长有关的新机制，因为大约一半的突变体影响以前没有详细研究过的基因。这些结果有望确定对C。白色念珠菌进行侵入性生长，并导致艾滋病患者的口咽念珠菌病。这些途径将在未来的研究中成为目标，以开发新的治疗方法。