Sexual reproduction and virulence of zygomycete fungi

接合菌的有性繁殖和毒力

• 批准号: 7990472
• 负责人: JOSEPH HEITMAN
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990472
• 关键词: Cell Death; Characteristics; Class Zygomycetes; Classification; Clinical; Communicable Diseases; Complex; Data; Diabetes Mellitus; Diagnostic; Disease; Drug Delivery Systems; Exhibits; Fertility; Fumaric acid; Gender Role; Gene Expression; Genes; Genetic; Genome; HMG Domain; Helicase Gene; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic stem cells; Homologous Gene; Human; Immunocompetent; Immunocompromised Host; Immunosuppressive Agents; Infection; Infertility; Inorganic Phosphate Transporter; Insecta; Knowledge; Laboratories; Lactate Dehydrogenase; Larva; Length; Life Cycle Stages; Link; Mating Types; Methodology; Methods; Modeling; Molecular Profiling; Moths; Mucor; Mucormycosis; Mus; Mycoses; Names; Organ Transplantation; Oryza; Pathogenesis; Pathogenicity; Patients; Pattern; Phagocytosis; Pharmaceutical Preparations; Phenotype; Phycomyces; Phylogeny; Predisposition; Proteins; Public Health; RNA Helicase; RNA Interference; Relative (related person); Reproduction; Reproduction spores; Resolution; Rhizopus; Risk Factors; Role; Sexual Development; Sexuality; Siblings; Solid; Sterility; Structure; System; Testing; Transplant Recipients; Trauma; Trioses; Virulence; Virulent; Waxes; Zygomycosis; base; cohort; cytotoxicity; fungus; homologous recombination; insight; interest; macrophage; mortality; mutant; novel; pathogen; public health relevance; sex; sexual relationship; trait; transcription factor; vpr Genes

DESCRIPTION (provided by applicant): Mucor circinelloides and Rhizopus oryzae are the most prevalent causal agents of the deadly fungal infection, mucormycosis, which is an emerging disease in immunocompromised patients and the second most common fungal infection in both hematopoietic malignancy patients and transplant recipients. However, considerably less is known about the virulence of these species compared to other fungal pathogens. This study focuses on the genetics of sexual development and pathogenicity of two zygomycete species complexes. In the studies proposed for M. circinelloides, we will investigate the roles of three genes that encode a triose phosphate transporter homolog, HMG domain protein, and RNA helicase in the syntenic sex locus of three related Mucor sub-species. The expression patterns of these genes during sexual development will be investigated. Disruption mutants of each gene and isogenic strains will be generated to test their roles in sexual development. Our recent studies found evidence that the sex locus may be involved in spore size and virulence of M. circinelloides, in which (-) isolates produce more virulent larger spores when compared to (+) isolates. We will investigate how genes in the syntenic sex locus are involved in spore size determination and virulence in three host models: cultured macrophages, the wax moth Galleria mellonella, and the mouse. In parallel, in the studies proposed for R. oryzae, we will establish a typing system to classify R. oryzae and R. delemar that are two sub-species in the R. oryzae complex. The two sub-species will be discriminated at high resolution based on MLST and lactate dehydrogenase gene sequences. Our preliminary studies indicate that R. oryzae is sexual and saprobic, whereas R. delemar is infertile under laboratory conditions and may be more virulent. We will also further test sexuality of the two sub-species as well as virulence in the wax moth and the mouse to investigate links between sexuality and virulence. Understanding the life cycles and detailed phylogeny of these pathogens will greatly enhance our knowledge to develop new drug targets and diagnostic typing approaches, and may provide the means to control human pathogenic zygomycetes. PUBLIC HEALTH RELEVANCE: Mucormycosis is an opportunistic fungal infection recently recognized as emerging cause of infectious disease with a high mortality rate. However, little is known about the relationship of sexual reproduction to pathogenesis in the zygomycetes compared to other fungal pathogens. This project will provide insight to develop novel drug targets, typing methodology to assign species causing infection, and information that can be applied to control zygomycete infections.

描述（由申请人提供）：卷枝毛霉和米根霉是致命真菌感染毛霉菌病最常见的病原体，毛霉菌病是免疫功能低下患者中的一种新发疾病，也是造血系统恶性肿瘤患者和移植受者中第二常见的真菌感染。然而，与其他真菌病原体相比，人们对这些物种的毒力知之甚少。这项研究的重点是两个接合菌物种复合体的性发育和致病性的遗传学。在针对卷曲毛霉的研究中，我们将研究编码丙糖磷酸转运蛋白同源物、HMG 结构域蛋白和 RNA 解旋酶的三个基因在三个相关毛霉亚种的同线性基因座中的作用。将研究这些基因在性发育过程中的表达模式。将产生每个基因和等基因菌株的破坏突变体以测试它们在性发育中的作用。我们最近的研究发现有证据表明，性位点可能与卷枝分枝杆菌的孢子大小和毒力有关，其中（-）分离株与（+）分离株相比，产生毒性更强的较大孢子。我们将研究同线性基因座中的基因如何参与三种宿主模型（培养的巨噬细胞、蜡蛾大蜡螟和小鼠）中的孢子大小决定和毒力。与此同时，在针对米根霉的研究中，我们将建立一个分型系统，对米根霉和米根霉复合体中的两个亚种进行分类。将根据 MLST 和乳酸脱氢酶基因序列以高分辨率区分这两个亚种。我们的初步研究表明，米根霉是有性且腐生的，而德莱马根霉在实验室条件下是不育的，并且可能具有更强的毒性。我们还将进一步测试这两个亚种的性行为以及蜡蛾和小鼠的毒力，以研究性行为和毒力之间的联系。了解这些病原体的生命周期和详细系统发育将极大地增强我们开发新药物靶点和诊断分型方法的知识，并可能提供控制人类致病接合菌的手段。 公共卫生相关性：毛霉菌病是一种机会性真菌感染，最近被认为是导致高死亡率传染病的新原因。然而，与其他真菌病原体相比，人们对接合菌的有性繁殖与发病机制的关系知之甚少。该项目将提供开发新药物靶点的见解、指定引起感染的物种的分型方法以及可用于控制接合菌感染的信息。