Role of genome plasticity in Candida albicans during host-pathogen interactions

白色念珠菌基因组可塑性在宿主与病原体相互作用过程中的作用

• 批准号: 8100921
• 负责人: Anja Forche
• 金额: $ 36.4万
• 依托单位: BOWDOIN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100921
• 关键词: AIDS/HIV problem; Address; Affect; Alleles; Animals; Antibiotic Therapy; Antigenic Variation; Benign; Blood; Blood Circulation; Cancer Patient; Candida albicans; Cause of Death; Cell Wall; Cell division; Chromosomes; Collection; Core Facility; DNA Sequence Rearrangement; Disease; Environment; Equilibrium; Event; Evolution; Exposure to; Flow Cytometry; Fungal Drug Resistance; Gene Amplification; Gene Conversion; Gene Expression; Gene Family; Generations; Genes; Genetic; Genetic Crossing Over; Genetic Recombination; Genetic Variation; Genome; Genomics; Genotype; Goals; Growth; Health; Human; Human body; Immune; Immune system; In Vitro; Indigenous; Individual; Infection; Length; Life; Location; Loss of Heterozygosity; Manuscripts; Medical; Membrane Proteins; Mitotic; Modeling; Mus; Mutation; Mycoses; Nutrient; Oral; Oral cavity; Organ; Organ Transplantation; Organism; Outcome; Patients; Phenotype; Play; Population; Process; Property; Public Health; Pulsed-Field Gel Electrophoresis; Research; Resources; Role; Single Nucleotide Polymorphism; Stream; Stress; Structure; Systemic infection; TAC1 gene; Tandem Repeat Sequences; Testing; Text; Time; Tissues; Vagina; Variant; Virulence; Work; chemotherapy; chromosome loss; comparative genomic hybridization; fitness; fungus; gastrointestinal; in vivo; insight; microorganism; novel; oropharyngeal thrush; pathogen

DESCRIPTION (provided by applicant): Candida albicans is a commensal fungus residing in the oral, gastrointestinal cavities, and the vagina of humans and other warm-blooded animals. It is also an opportunistic pathogen with a disease spectrum ranging from mild superficial infections in overall healthy people to wide-spread, deep-seated and life-threatening infections in patients who's immune system is severely compromised by underlying disease. C. albicans is the 4th most common microorganism causing nosocomial blood stream infections representing a serious public health challenge of increasing medical and socio-economical importance In previous work, we detected higher rates of phenotypic and chromosome-level genetic variation following passage of C. albicans in vivo than after propagation for a similar number of generations in vitro. In contrast, the rate of short-range recombination (LOH) events per cell division was similar following passage in vivo and in vitro. We concluded that conditions during infectious growth affect chromosome disjunction more strongly than they affect mitotic cross-over or other recombination processes and that the differing spectrum of short- and long-range LOH events must reflect the different selective environment represented by in vitro vs in vivo propagation. We are just beginning to understand by which mechanisms C. albicans adapts to different host environments, whether these changes are triggered by the host, and how the fungus modulates antigenic properties through variations of surface proteins. Our working hypothesis is that the adaptation of C. albicans through genetic changes during infection may play a bigger than anticipated role in host-pathogen interactions. Our goal is to study what is necessary to maintain the host-pathogen balance from the perspective of the fungus. In particular, how do the high levels of genetic and phenotypic variation that we find in strains exposed to the host affect the fitness of the fungus and how do such alterations in fitness influence the host-pathogen interaction. We will study two large post-in vivo sets of isolates from an oropharyngeal candidiasis (OPC) model and a blood stream infection (BSI) model to address several important questions in this proposal: 1) Do host niches such as the oral cavity and bloodstream cause similar types of increased genetic and phenotypic diversity? 2) Does exposure to host niches induce novel genotypes? 3) Does growth in the host select for altered fitness and or virulence? and 4) Do cell wall associated genes contribute to antigenic variation? Our studies will advance our understanding of host-pathogen interactions from the pathogen's perspective and will aid us in revealing how the host and the fungus maintain their balanced relationship in healthy individuals as well as how disruption of this interaction causes devastating infections in the immuno-compromised host. PUBLIC HEALTH RELEVANCE: Fungal infections are a serious health concern for immuno-compromised patients, such as those with HIV/AIDS, cancer patients or patients receiving organ transplants. Fungal infections occur at many body locations and can infect virtually all organs in the human body. The proposed work will address basic questions on host-fungus interactions with the goal of advancing our understanding of how the host and the fungus maintain their balanced relationship in healthy individuals as well as how disruption of this interaction causes devastating infections in the immuno-compromised host.

描述（由申请人提供）：白色念珠菌是一种共生真菌，存在于人类和其他温血动物的口腔、胃肠腔和阴道中。它也是一种机会性病原体，其疾病范围从总体健康人群的轻度表面感染到免疫系统因潜在疾病严重受损的患者的广泛、根深蒂固和危及生命的感染。白色念珠菌是引起医院血流感染的第四大常见微生物，对公共卫生构成了严重的挑战，具有日益重要的医学和社会经济意义。在之前的工作中，我们发现体内白色念珠菌传代后的表型和染色体水平遗传变异率高于体外繁殖相同数量的念珠菌传代后的遗传变异率。相比之下，每个细胞分裂的短程重组（LOH）事件在体内和体外传代后相似。我们得出的结论是，感染生长过程中的条件对染色体分离的影响比对有丝分裂交叉或其他重组过程的影响更大，并且短期和长期LOH事件的不同光谱必须反映出体外和体内繁殖所代表的不同选择环境。我们刚刚开始了解白色念珠菌适应不同宿主环境的机制，这些变化是否由宿主触发，以及真菌如何通过表面蛋白的变化调节抗原特性。我们的工作假设是白色念珠菌在感染过程中通过遗传变化的适应性可能在宿主-病原体相互作用中发挥比预期更大的作用。我们的目标是从真菌的角度研究维持宿主-病原体平衡所必需的条件。特别是，我们在暴露于宿主的菌株中发现的高水平遗传和表型变异如何影响真菌的适应性，以及适应性的这种改变如何影响宿主-病原体相互作用。我们将研究来自口咽念珠菌病（OPC）模型和血流感染（BSI）模型的两组大型体外分离物，以解决本提案中的几个重要问题：1)宿主生态位（如口腔和血液）是否会导致类似类型的遗传和表型多样性增加？2)暴露于宿主生态位是否会诱发新的基因型？3)宿主的生长是否选择改变适应性和/或毒力？细胞壁相关基因是否会导致抗原变异？我们的研究将从病原体的角度推进我们对宿主-病原体相互作用的理解，并将帮助我们揭示宿主和真菌如何在健康个体中维持其平衡关系，以及这种相互作用的破坏如何导致免疫受损宿主的破坏性感染。