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。组抑素是由人类唾液腺分泌的小分子量肽家族，参与口腔的非免疫防御。组蛋白5 （Hst-5）是主要的唾液保护成分，具有有效的抗真菌特性，在艾滋病患者的唾液中减少。白念珠菌细胞壁Hst-5受体为热休克蛋白70。热休克蛋白70结合并运输Hst-5分子，将其传递到细胞靶点。因此，酵母细胞表面的变化可以影响细胞壁蛋白和表面受体表达的调控。C. dubliniensis是一种主要从HIV+和艾滋病患者中分离出来的物种，具有快速产生耐药性的能力。与白色念珠菌相比，都柏林念珠菌具有不同形态和组成的细胞壁。这些特性可能有助于它作为机会性病原体的出现，能够避开宿主的防御机制，形成生物膜并在口腔中定植。本研究将验证以下假设：(A) C. dubliniensis细胞壁上的修饰部分参与了C. dubliniensis对Hst-5、Hsp70受体的下调，从而降低了C. dubliniensis对Hst-5的易感性；(B) C. dubliniensis在HIV+患者中首选的口腔酵母定殖与宿主唾液组蛋白水平降低和Hsp70真菌表达减少有关。计划有两个目标：1。测定Hsp70在c .白色念珠菌和c . dubliniensis中的表达(a)全细胞裂解物和(b)两种酵母细胞的细胞质和细胞壁部分，以及(c)在室温和37℃下生长的c . dubliniensis和c .白色念珠菌与提取细胞壁的c .白色念珠菌细胞对Hst-5的敏感性。2. (a)测定并比较20名艾滋病毒阳性口腔念珠菌病患者（10名dublinic和10名白色念珠菌）和匹配健康对照组唾液中Hst-5的水平(b)测定并比较从艾滋病毒阳性个体中恢复的dublinic和白色念珠菌分离株对Hst-5的易感性。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认识。这些数据将有助于提高我们对真菌毒力因子如何增强口腔组织生物膜形成的理解，当这些因素与改变的非特异性宿主粘膜防御同时发生时，允许优先选择具有已证实适应性的物种，如C. dubliniensis。

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.