Receptor Affects Fungal Mucosal Colonization in HIV

受体影响 HIV 中真菌粘膜定植

基本信息

批准号：
6915766
负责人：
MARY ANN Y JABRA-RIZK
金额：
$ 7.43万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2007-04-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：口腔是 HIV+ 患者机会性感染的主要目标。组氨酸是人类唾液腺分泌的一类小分子量肽，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，并且在艾滋病患者的唾液中含量减少。白色念珠菌细胞壁上的 Hst-5 受体被鉴定为热休克蛋白 70。热休克蛋白 70 结合并转运 Hst-5 分子，将其递送至其细胞靶点。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。都柏林念珠菌是一种主要从 HIV+ 和 AIDS 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其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殖。该提案将检验以下假设：(A) C. dubliniensis 细胞壁的修饰部分包括 Hst-5、Hsp70 受体的下调，从而降低 C. dubliniensis 对 Hst-5 的敏感性(B) 都柏林念珠菌优先在 HIV+ 患者中定植口腔酵母，这与宿主唾液组蛋白水平降低和 Hsp70 真菌表达最小有关。计划实现两个目标： 1. 确定白色念珠菌和都柏林念珠菌中 Hsp70 的表达 (a) 全细胞裂解物和 (b) 两个物种酵母细胞的胞质和细胞壁部分，以及 (c) 确定对 Hst 的敏感性与提取细胞壁的白色念珠菌细胞相比，在室温和 37 摄氏度下生长的都柏林念珠菌和白色念珠菌细胞的数量为 -5。 2. (a) 确定并比较 20 名 HIV+ 口腔念珠菌病患者（10 名都柏林念珠菌，10 名白色念珠菌）和匹配的健康对照组的唾液 Hst-5 水平 (b) 确定并比较敏感性从 HIV+ 个体中回收的都柏林念珠菌和白色念珠菌分离株的 Hst-5。完成这些目标将提供新的数据，扩展我们与艾滋病毒患者真菌感染相关的知识。这些数据将有助于加深我们对当真菌毒力因子与非特异性宿主粘膜防御改变同时发生时，真菌毒力因子如何增强口腔组织生物膜形成的理解，从而允许优先选择具有经过证明的适应性的物种，例如都柏林念珠菌。