Chromosome copy number variation and AIDS-associated cryptococcosis

染色体拷贝数变异和艾滋病相关隐球菌病

• 批准号: 7679357
• 负责人: JAMES W KRONSTAD
• 金额: $ 14.65万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679357
• 关键词: Acquired Immunodeficiency Syndrome; Antifungal Agents; Antifungal Therapy; Breathing; Cells; Cerebrospinal Fluid; Cerebrum; Chromosomes; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 4; Clinical; Copy Number Polymorphism; Cryptococcus neoformans; Cryptococcus neoformans infection; DNA; Disease; Disease Outcome; Drug resistance; Environment; Frequencies; Genetic; Genome; Genomics; Goals; Growth; HIV; Human; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Incidence; Infection; Life; Link; Literature; Melanins; Meningitis; Meningoencephalitis; Modeling; Mus; Mycoses; Patients; Phenotype; Predisposition; Process; Production; Property; Relapse; Research; Risk; Sampling; Serotyping; Source; Temperature; Testing; Therapeutic Intervention; Therapeutic immunosuppression; Treatment Failure; Variant; Virulence; Virulence Factors; Work; capsule; combat; fungus; interest; mouse model; novel; pathogen; prevent; public health relevance; trait

DESCRIPTION (provided by applicant): The fungal pathogen Cryptococcus neoformans causes a high incidence of life-threatening infections leading to meningitis in AIDS patients, and this fungus is therefore a major threat to the > 40 million people worldwide who are infected with HIV. In addition, the related species C. gattii has recently emerged as threat to immunocompetent people. The infections caused by these fungi are difficult to treat because the pathogens persist in the body, and it is often necessary to maintain patients on life long antifungal therapy to prevent relapse. It is likely that pathogen persistence involves specific adaptations to the host environment that may allow the fungus to withstand the immune response and to resist therapeutic intervention. It is also known that pathogen variation during infection can have a major impact on disease outcome by influencing virulence factor expression, drug resistance and evasion of the immune response. We have discovered a novel mechanism of genomic variation in C. neoformans that may contribute to disease outcome in immunocompromised people. Specifically, we found that a clinical isolate of C. neoformans from an AIDS patient shows copy number variation for chromosome 13 that correlates with variable expression of the virulence factor melanin. That is, loss of melanin production in variants is associated with copy number variation for chromosome 13 and we hypothesize that copy number variants have different virulence properties. Our first aim for the proposed exploratory work is to determine whether copy number variation at chromosome 13 is relevant to the virulence of C. neoformans by testing variants in a mouse model of cryptococcosis. We will also determine whether growth of the pathogen in the host influences the frequency of copy number changes for chromosome 13. Our second aim is to establish a more thorough understanding of copy number variation for all of the chromosomes by examining additional strains from AIDS patients and from environmental sources. We will also use existing samples to examine DNA isolated directly from C. neoformans cells in the cerebral spinal fluid of infected AIDS patients. The results of this work will provide a deeper understanding of C. neoformans variation during infection and contribute to the long- term goal of developing new strategies to combat fungal infections. PUBLIC HEALTH RELEVANCE: The relevance of this project comes from the pressing need to control fungal infections in humans that have impaired immune systems due to AIDS or immunosuppressive therapy. The 40 million or more people infected with HIV are at particular risk of succumbing to fungal disease. The proposed research will specifically examine the ability of a fungal pathogen to vary its genetic make up during the infection process. Pathogen variation may contribute to persistence during infection and treatment failure.

描述（由申请人提供）：真菌病原体新型隐球菌导致危及生命的感染的高发病率，导致艾滋病患者的脑膜炎，因此这种真菌是全世界超过4000万艾滋病毒感染者的主要威胁。此外，近缘种C.格特最近已经成为对免疫能力正常的人的威胁。由这些真菌引起的感染很难治疗，因为病原体在体内持续存在，并且通常需要维持患者终身抗真菌治疗以防止复发。病原体持续存在可能涉及对宿主环境的特定适应，这可能使真菌能够承受免疫反应并抵抗治疗干预。还已知感染期间的病原体变异可通过影响毒力因子表达、耐药性和免疫应答逃避而对疾病结果产生重大影响。我们发现了C.可能导致免疫功能低下人群疾病结局的新生儿。特别是，我们发现临床分离的C。来自AIDS患者的新生儿显示出与毒力因子黑色素的可变表达相关的13号染色体的拷贝数变异。也就是说，变异体中黑色素产生的损失与13号染色体的拷贝数变异相关，我们假设拷贝数变异体具有不同的毒力特性。我们的第一个目标是探索性的工作，以确定是否在13号染色体的拷贝数变异是相关的毒力的C。通过在隐球菌病小鼠模型中测试变异体来检测新型隐球菌。我们还将确定病原体在宿主中的生长是否影响13号染色体拷贝数变化的频率。我们的第二个目标是通过检查来自艾滋病患者和环境来源的其他菌株，建立对所有染色体拷贝数变异的更透彻的理解。我们还将使用现有的样本来检测直接从C.艾滋病患者脑脊液中的新生儿细胞。这些工作的结果将有助于更深入地了解C。新形菌在感染过程中的变异，并有助于发展新的战略，以打击真菌感染的长期目标。公共卫生相关性：该项目的相关性来自于控制人类真菌感染的迫切需要，这些真菌感染由于艾滋病或免疫抑制治疗而损害了免疫系统。4000万或更多感染艾滋病毒的人特别容易死于真菌疾病。拟议的研究将专门研究真菌病原体在感染过程中改变其遗传组成的能力。病原体变异可能导致感染持续存在和治疗失败。