Receptor Affects Fungal Mucosal Colonization in HIV

受体影响 HIV 中真菌粘膜定植

• 批准号: 6841772
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841772
• 关键词: Candida; Candida albicans; HIV infections; SDS polyacrylamide gel electrophoresis; antifungal agents; biofilm; candidiasis; cell wall; clinical research; densitometry; heat shock proteins; human subject; monoclonal antibody; mucosal immunity; oral mucosa; protein localization; protein structure function; receptor expression; saliva

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靶点。组胺素是一类由人唾液腺分泌的小分子量多肽，参与口腔的非免疫防御。组胺素5（Hst-5）是具有强效抗真菌特性的主要保护性唾液成分，并且在艾滋病患者的唾液中减少。C.白念珠菌细胞壁热休克蛋白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标。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节。C. Dubliniensis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C.白色念珠菌、C. dubliniensis表现出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致病菌的出现，能够避开宿主的防御机制，形成生物膜并在口腔中定植。这一提议将检验以下假设：（A）C. Dubliniensis对C. dubliniensis的易感性部分在于Hst-5、Hsp 70受体的下调，从而降低C. dubliniensis的易感性。dubliniensis对Hst-5（B）口腔酵母的定殖。Dubliniensis优先在HIV+患者中与宿主唾液组胺素水平降低和Hsp 70的最小真菌表达有关。计划有两个目标：1。检测热休克蛋白70在C.白色念珠菌和C. dubliniensis（a）全细胞裂解物和（B）两个物种的酵母细胞的胞质和细胞壁部分和（c）确定C. dubliniensis和C.在室温和37 ℃下生长的白色念珠菌与C.具有提取的细胞壁的白色念珠菌细胞。2. (a)对20例HIV阳性的口腔念珠菌病患者（10例为念珠菌感染）唾液Hst-5水平进行了测定和比较。dubliniensis和C.白色念珠菌）和匹配的健康对照组（B）测定并比较念珠菌对Hst-5的敏感性。dubliniensis和C.从HIV+个体中回收的白色念珠菌分离株。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。这些数据将有助于我们进一步了解真菌毒力因子如何增强口腔组织上生物膜的形成，当这些因子与改变的非特异性宿主粘膜防御同时发生时，允许具有已证明适应性的物种，如C。优先选择Dubliniensis。