Receptor Affects Fungal Mucosal Colonization in HIV

描述(由申请人提供)：口腔是HIV+患者机会性感染的主要目标。组蛋白是由人类唾液腺分泌的一类小分子多肽，参与口腔的非免疫防御。组织蛋白5(HST-5)是主要的保护唾液成分，具有强大的抗真菌特性，在艾滋病患者的唾液中减少。白念珠菌细胞壁上的HST-5受体被鉴定为热休克蛋白70。热休克蛋白70结合并运输HST-5分子，将其传递到其细胞靶点。因此，酵母细胞表面的变化可能会影响细胞壁蛋白和表面受体表达的调节。都柏林锥虫是一种主要从HIV+和艾滋病患者中分离出来的物种，具有迅速产生抗药性的能力。与白色念珠菌相比，都柏林念珠菌的细胞壁具有不同的形态和组成。这些特性可能有助于它成为一种机会性病原体，能够避开宿主的防御机制，形成生物膜，并在口腔中定居。这一建议将检验这样的假设：(A)都柏林弯曲霉细胞壁的修饰部分包括对HST-5，HSP70受体的下调，这反过来又降低了都柏林弯曲霉对HST-5的易感性。(B)都柏林弯曲霉在HIV+患者中的口服酵母定植优先与宿主唾液组织蛋白水平降低和HSP70的最低真菌表达有关。计划有两个目标：1.确定HSP70在白念珠菌和都柏林念珠菌中的表达(A)整个细胞裂解产物和(B)这两个物种酵母细胞的胞液和细胞壁部分，以及(C)确定在室温和37℃下生长的都柏林念珠菌和白色念珠菌对HST-5的敏感性，并与提取细胞壁的白色念珠菌的细胞进行比较。2.(A)测定和比较20例HIV阳性口腔念珠菌病患者(10例都柏林念珠菌和10例白色念珠菌感染)和10例健康对照组唾液中HST-5的水平；(B)测定和比较从HIV阳性患者中分离到的两种念珠菌对HST-5的敏感性。完成这些目标将提供新的数据，扩展我们对艾滋病毒患者真菌感染的相关知识。这些数据将有助于我们理解，当真菌毒力因子与改变的非特异性宿主粘膜防御同时发生时，这些因子如何促进口腔组织上生物膜的形成，从而使具有已被证明的适应性的物种被优先选择。

DESCRIPTION (provided by applicant): The oral cavity is a primary target for opportunistic infections in HIV+ patients. Histatins are a family of small molecular weight peptides secreted by human salivary glands that participate in nonimmune defense of the oral cavity. Histatin 5 (Hst-5) is the primary protective salivary component with potent antifungal properties and reduced in the saliva of AIDS patients. The receptor of Hst-5 on C. albicans cell wall was identified as heat shock protein 70. Heat shock protein 70 binds and transports the Hst-5 molecule delivering it to its cellular target. Therefore, changes in the yeast cell surface could affect the regulation of cell wall proteins and surface receptor expression. C. dubliniensis is a species that has been isolated primarily from HIV+ and AIDS patients and has the ability to rapidly develop drug resistance. In comparison to C. albicans, C. dubliniensis was shown to posses a cell wall with different morphology and composition. These properties could have aided its emergence as an opportunistic pathogen, capable of avoiding host's defense mechanisms, forming biofilms and colonizing the oral cavity. This proposal will test the hypothesis that (A) the modifications in the cell wall of C. dubliniensis consist in part of the down regulation of the receptor to Hst-5, Hsp70 which in turn reduces the susceptibility of C. dubliniensis to Hst-5 (B) oral yeast colonization by C. dubliniensis preferentially in HIV+ patients is related to decreased host salivary histatin levels and minimal fungal expression of Hsp70. Two aims are planned: 1. Determine the expression of Hsp70 in C. albicans and C. dubliniensis (a) whole cell lysates and (b) cytosolic and cell wall fractions of the yeast cell for both species and (c) Determine susceptibility to Hst-5 of C. dubliniensis and C. albicans grown at room temperature and 37 degrees C in comparison to those of C. albicans cells with extracted cell walls. 2. (a) Determine and compare the levels of salivary Hst-5 in 20 HIV+ patients with oral candidiasis (10 with C. dubliniensis and 10 with C. albicans) and in a matched healthy control group (b) Determine and compare the susceptibility to Hst-5 of the C. dubliniensis and C. albicans isolates recovered from the HIV+ individuals. Completing these aims will provide novel data extending our knowledge related to fungal infections in HIV patients. These data will help to advance our understanding of how fungal virulence factors enhance biofilm formation on oral tissues when these facors occur simultaneously with altered non specific host mucosal defenses, allowing species with proven adaptability such as C. dubliniensis to be preferentially selected.