Genetics of trans-kingdom interactions between Candida and bacteria

描述(申请人提供)：念珠菌被认为是重症监护病房内医院获得性感染的主要原因之一，以及困扰免疫抑制的个人，如艾滋病毒阳性患者。念珠菌利用多种毒力因子对宿主进行定植和感染。念珠菌是机会真菌，通常不会对健康的人造成感染。通常，重症监护病房中念珠菌的感染与当前细菌的抗菌治疗有关。 感染。假丝酵母菌的这种表现很可能是由于无意中杀死了 允许真菌生长的身体。与白色念珠菌有关的多菌感染影响了近27%的患者。最近的研究表明，白念珠菌和细菌可以通过识别白念珠菌和白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，白色念珠菌含有几个基因决定因素，使它能够感知并对宿主环境中与其相互作用的大多数细菌物种做出反应。在这项研究中，我们将研究白色念珠菌的十个基因，它们在念珠菌与细菌的相互作用中发挥作用，我们从先前筛选的18,000株白色念珠菌突变文库中鉴定出在选择的细菌存在时是否有能力形成丝状结构。由于这些基因突变是通过在细菌存在的情况下进行共培养来鉴定的，我们也选择了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。我们还将确定假丝酵母菌接触细菌时所选基因的时间表达。突变菌株将在细菌存在或不存在的情况下培养，以确定基因表达是结构性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来确定这些选定菌株的毒力属性。 这项研究的短期益处将有助于对念珠菌与各种细菌相互作用的过程有一个基本的了解。了解哪些遗传决定因素对念珠菌与细菌的相互作用是重要的，这将有助于开发新的细菌分子用于抗真菌开发。在识别新的抗真菌或抗生素化合物的许多条件下，科学家往往会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。就我们目前对人类微生物群及其组织如何影响人类健康的兴趣而言，这可能会为新化合物打开一扇新的大门，这些化合物可以直接针对白念珠菌的生长，而不会破坏其他必要的微生物区系 维持与人类宿主的动态平衡。从长远来看，有可能开发出新的抗菌剂，这些抗菌剂可以单独使用，也可以与目前的治疗方法结合使用，用于治疗真菌感染。

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.