Genetics of trans-kingdom interactions between Candida and bacteria

念珠菌和细菌之间跨界相互作用的遗传学

• 批准号: 8768858
• 负责人: MICHAEL D KRUPPA
• 金额: $ 42.2万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768858
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antibiotics; Antifungal Agents; Bacteria; Bacterial Infections; Biological; Biological Models; Caenorhabditis elegans; Candida; Candida albicans; Coculture Techniques; Communication; Communities; Complex Mixtures; Critical Care; Critical Illness; Development; Environment; Experimental Models; Farnesol; Filament; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Screening; Genome; Growth; HIV; HIV Seropositivity; Health; Homeostasis; Human; Human Microbiome; Human body; Hyphae; Immune; Immune system; Immunocompromised Host; Incubated; Individual; Infection; Infectious Agent; Invertebrates; Libraries; Location; Maps; Measures; Mediating; Microbe; Microbial Biofilms; Modeling; Mus; Mycoses; Pathway interactions; Patients; Penetration; Phenotype; Play; Polymerase Chain Reaction; Process; Proteins; Pseudomonas aeruginosa; RNA; Regulation; Reverse Transcription; Role; Scientist; Soil; Staphylococcus aureus; Surface; System; Testing; Transcript; Virulence; Virulence Factors; Water; Yeasts; antimicrobial; antimicrobial drug; behavior influence; design; drug development; fungus; genetic element; in vivo; inhibitor/antagonist; innovation; insight; interest; killings; mortality; mutant; novel; pathogen; public health relevance; quorum sensing; response; screening; ward

DESCRIPTION (provided by applicant): Candida species are considered to be one of the leading causes of nosocomial acquired infections within critical care units, as well as afflicting immune suppressed individuals such as HIV positive patients. Candida utilizes a variety of virulence factors for colonization and infection of the host. Candida species are opportunistic fungi, which normally do not cause infection in healthy individuals. Oftentimes, infection with Candida in the critical care ward is associated with antimicrobial treatment of a current bacterial infection. This presentation of Candida is likely due to inadvertent killing of the normal flora in the body allowing for growth of the fungus. Polymicrobial infections involving C. albicans affect almost 27% of patients. It has recently been demonstrated that C. albicans and bacteria can affect each other's biological activities through the recognition of quorum sensing molecules secreted by both the bacteria and C. albicans. The primary hypothesis of this study is that Candida albicans harbors several genetic determinants that allow it to sense and respond to the majority of bacterial species with which it interact within the host environment. In this study we will investigate ten genes from C. albicans that play a role in Candida-bacterial interactions we identified from previous screen of a mutant library of 18,000 C. albicans strains for the ability t filament in the presence of select bacteria. As these genetic mutants were identified by co-cultivation in the presence of bacteria, we have also chosen to test the candidate strains against a panel of known bacterial secreted molecules in order to categorize the appropriate response pathway. We will also determine the temporal expression of the selected genes when Candida is exposed to bacteria. Mutant strains will be grown in the presence or absence of bacteria to determine if gene expression is constitutive or induced by the presence of bacteria. We will also ascertain the virulence attributes of these selected strains using an invertebrate infection model. The short term benefits from this study will help in providing a basic understanding of the process by which Candida interacts with various bacterial species. Understanding what genetic determinants are important for Candida-bacterial interactions will be useful for exploiting novel bacterial molecules for antifungal development. Under many conditions for identifying new antifungal or antibiotic compounds, scientists tend to explore the environments of the soil and water and other ecological niches for new compounds, but have not looked at the microbes within the human body. In our case with the current interest in the human microbiome and how its organization affects human health, this could open a new door for novel compounds that could directly target C. albicans growth without disrupting other microflora that are necessary for maintaining homeostasis with the human host. In the long-term, there is the potential for development of novel antimicrobial agents that could be used either alone or in combination with current therapies for treatment of fungal infections.

描述（由申请人提供）：念珠菌属物种被认为是重症监护病房内院内获得性感染以及困扰免疫抑制个体（例如 HIV 阳性患者）的主要原因之一。念珠菌利用多种毒力因子来定植和感染宿主。念珠菌属机会性真菌，通常不会引起健康个体感染。通常，重症监护病房的念珠菌感染与当前细菌的抗菌治疗有关 感染。念珠菌的这种表现可能是由于无意中杀死了体内的正常菌群所致。 身体允许真菌生长。涉及白色念珠菌的多种微生物感染影响了近 27% 的患者。最近已经证明，白色念珠菌和细菌可以通过识别细菌和白色念珠菌分泌的群体感应分子来影响彼此的生物活性。这项研究的主要假设是白色念珠菌具有多种遗传决定因素，使其能够感知宿主环境中与其相互作用的大多数细菌物种并对其做出反应。在这项研究中，我们将研究来自白色念珠菌的 10 个基因，这些基因在念珠菌-细菌相互作用中发挥作用，我们是从先前筛选的 18,000 个白色念珠菌菌株的突变体库中鉴定出的，以了解在特定细菌存在下的 t 丝能力。由于这些基因突变体是通过在细菌存在下共培养来鉴定的，因此我们还选择针对一组已知的细菌分泌分子来测试候选菌株，以便对适当的反应途径进行分类。当念珠菌暴露于细菌时，我们还将确定所选基因的时间表达。突变菌株将在存在或不存在细菌的情况下生长，以确定基因表达是组成型的还是由细菌的存在诱导的。我们还将使用无脊椎动物感染模型确定这些选定菌株的毒力属性。 这项研究的短期效益将有助于提供对念珠菌与各种细菌相互作用过程的基本了解。了解哪些遗传决定因素对念珠菌-细菌相互作用很重要，将有助于开发新的细菌分子来开发抗真菌药物。在识别新的抗真菌或抗生素化合物的许多条件下，科学家倾向于探索土壤和水的环境以及其他生态位来寻找新的化合物，但没有研究人体内的微生物。就我们而言，目前人们对人类微生物组及其组织如何影响人类健康感兴趣，这可能为新型化合物打开一扇新的大门，这些化合物可以直接针对白色念珠菌的生长，而不破坏白色念珠菌生长所需的其他微生物群落。 维持与人类宿主的体内平衡。从长远来看，有开发新型抗菌药物的潜力，这些药物可以单独使用或与当前的真菌感染疗法联合使用。