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）：白色念珠菌是一种居住在口腔，胃肠道腔内的共生真菌，人类和其他温水动物的阴道。它也是一种机会性病原体，其疾病范围从整体健康患者的轻度表面感染到广泛，深处且威胁生命的感染因免疫系统而受到严重损害。白色念珠菌是第四最常见的微生物，引起了医院血流感染，代表了以前工作中医学和社会经济重要性提高医学和社会经济重要性的严重挑战，我们发现表型和染色体水平的遗传差异率高于在传播后，比起在Vivo中，C. bac C. c. c. c. c. c. c. cc. after的生物均与类似的生物相似。相比之下，在体内和体外通过后，每个细胞分裂的短距离重组（LOH）事件的发生率相似。我们得出的结论是，感染生长期间的条件影响染色体的分离比影响有丝分裂的交叉或其他重组过程更强烈，并且短期和长期LOH事件的不同频谱必须反映出体内体内体外VS代表的不同选择环境。我们才刚刚开始了解哪些机制C.白色念珠菌适应不同的宿主环境，这些变化是否是由宿主触发的，以及真菌如何通过表面蛋白的变化来调节抗原性能。我们的工作假设是，在感染过程中，白色念珠菌通过遗传变化的适应可能比预期的宿主 - 病原体相互作用更大。我们的目标是研究从真菌的角度来维持宿主 - 病原体平衡的必要条件。特别是，我们在暴露于宿主的菌株中发现的高水平的遗传和表型变异会影响真菌的适应性，以及适应性的这种改变如何影响宿主 - 病原体的相互作用。我们将研究来自口咽念珠菌病（OPC）模型和血流感染（BSI）模型的两种大型体内分离株，以解决该提案中的几个重要问题：1）宿主宿主的生态障碍是否会导致口腔和血液等类型类型会导致类似类型的遗传和表型多样性？ 2）暴露于宿主壁nir会诱导新的基因型吗？ 3）宿主的生长是否选择改变适应性和或毒力？ 4）细胞壁相关基因是否有助于抗原差异？我们的研究将从病原体的角度提高我们对宿主病原体相互作用的理解，并将有助于我们揭示宿主和真菌如何在健康个体中保持平衡的关系以及这种相互作用的破坏如何引起免疫繁殖宿主的毁灭性感染。 公共卫生相关性：真菌感染对免疫受损患者（例如患有艾滋病毒/艾滋病患者，癌症患者或接受器官移植的患者的患者）的严重健康关注。真菌感染发生在许多身体位置，并且几乎可以感染人体中的所有器官。拟议的工作将解决有关宿主 - 康加斯相互作用的基本问题，目的是促进我们对宿主和真菌如何保持他们在健康个体中如何保持平衡关系的理解，以及这种相互作用的破坏如何导致免疫强化宿主的毁灭性感染。