Role of genome plasticity in Candida albicans host-pathogen interactions

基因组可塑性在白色念珠菌宿主-病原体相互作用中的作用

• 批准号: 8689434
• 负责人: Anja Forche
• 金额: $ 36.63万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689434
• 关键词: AIDS/HIV problem; Address; Affect; Animals; Antibiotic Therapy; Benign; Blood; Cancer Patient; Candida albicans; Cause of Death; Chromosomes; Core Facility; DNA; DNA Sequence Rearrangement; Disease; Environment; Equilibrium; Event; Evolution; Exposure to; Funding; Gastrointestinal tract structure; Generations; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Growth; Haploidy; Health; Human; Human body; Immune; Immune system; Immunity; In Vitro; Indigenous; Individual; Infection; Lead; Life; Location; Loss of Heterozygosity; Manuscripts; Medical; Membrane Proteins; Mitotic Recombination; Modeling; Mus; Mutation; Mycoses; Oral cavity; Organ; Organ Transplantation; Organism; Outcome; Pathogenicity; Patients; Phenotype; Play; Ploidies; Population; Process; Public Health; Research; Resources; Role; Severities; Single Nucleotide Polymorphism; Site; Stream; Stress; Systemic infection; Testing; Text; Therapeutic immunosuppression; Tissues; Vagina; Variant; Virulence; Work; chemotherapy; comparative genomic hybridization; fitness; fungus; genome sequencing; genome-wide; in vivo; insight; microorganism; mouse model; novel; oropharyngeal thrush; pathogen; progenitor; public health relevance; research study; response; socioeconomics

DESCRIPTION (provided by applicant): Candida albicans is a commensal fungus residing in the oral cavity, the gastrointestinal tract, 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, and life-threatening systemic infections in patients with compromised immunity due to underlying disease or immunosuppressive therapy. C. albicans is the 4th most common microorganism causing nosocomial blood stream infections, therefore representing a serious public health challenge of increasing medical and socio-economic importance. 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. 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, while the rate of short-range loss of heterozygosity (LOH) due to recombination was similar following passage in vivo and in vitro. We concluded that conditions encountered during infectious growth affect chromosome (Chr) disjunction more strongly than they affect mitotic recombination processes and that the differing spectrum of short- and long-range LOH events must reflect a difference in the selective environment represented by in vitro versus in vivo propagation. We are just beginning to understand how C. albicans adapts to varying host environments, whether adaptations are triggered by the host, and how the fungus modulates antigenicity through variations in its surface proteins. Our goal is to better understand what is necessary to maintain the pathogen-host balance from the perspective of the fungus, and to identify changes that will tip this balance towards pathogenicity. Recently, we showed that high levels of genetic change in C. albicans after exposure to a mouse host resulted in noticeable alterations in phenotype, including phenotypes associated with virulence. In this proposal we seek to understand how the high levels of genetic and phenotypic variation that we find in such strains affect the fitness of the fungus, and how these alterations in fitness influence host-pathogen interactions. We will continue our study of two 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) What are the genomic changes that lead to alterations in major virulence-associated phenotypes? 2) How do genetic changes arising in one host environment affect the ability to adapt to a new host niche? 3) How well does in vitro fitness correlate with in vivo fitness? and 4) Are there specific genotypes that allow preferential colonization of particular organs? These studies will advance our understanding of host-pathogen interactions from the pathogen perspective and will help reveal 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、胃肠道和阴道中。它也是一种机会性病原体，其疾病谱范围从整体健康人群中的轻度浅表感染到因基础疾病或免疫抑制治疗而免疫力受损的患者中广泛的、危及生命的全身感染。白色念珠菌是导致医院血流感染的第四大常见微生物，因此代表着日益增加的医疗和社会经济重要性的严重公共卫生挑战。我们的工作假设是，白色念珠菌在感染过程中通过基因变化进行的适应可能在宿主与病原体的相互作用中发挥比预期更大的作用。在之前的工作中，我们检测到白色念珠菌在体内传代后的表型和染色体水平遗传变异率高于在体外繁殖相似代数后的比率，而由于重组而导致的短程杂合性丢失（LOH）率在体内和体外传代后相似。我们得出的结论是，感染性生长过程中遇到的条件对染色体 (Chr) 分离的影响比对有丝分裂重组过程的影响更大，并且短程和长程 LOH 事件的不同谱必定反映了体外与体内传播所代表的选择性环境的差异。我们才刚刚开始了解白色念珠菌如何适应不同的宿主环境，适应是否由宿主触发，以及真菌如何通过其表面蛋白的变化来调节抗原性。我们的目标是从真菌的角度更好地了解维持病原体-宿主平衡所必需的条件，并确定能够打破这种平衡的变化 走向致病性。最近，我们发现白色念珠菌在暴露于小鼠宿主后发生高水平的遗传变化，导致表型发生明显改变，包括与毒力相关的表型。在本提案中，我们试图了解在此类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，以及这些适应性的改变如何影响宿主与病原体的相互作用。我们将继续对来自口咽念珠菌病（OPC）模型和血流感染（BSI）模型的两组分离株进行研究，以解决本提案中的几个重要问题：1）哪些基因组变化导致主要毒力相关表型的改变？ 2) 一种宿主环境中发生的遗传变化如何影响适应新宿主生态位的能力？ 3) 体外健康与体内健康的相关性如何？和 4) 是否存在允许特定器官优先定植的特定基因型？这些研究将增进我们从病原体角度对宿主与病原体相互作用的理解，并将有助于揭示宿主和真菌如何在健康个体中维持平衡关系，以及这种相互作用的破坏如何导致免疫受损宿主的毁灭性感染。