HIV Modulates Oral Mucosal Calprotectin and Candidiasis

描述（由申请人提供）： 钙卫蛋白是由鳞状粘膜上皮细胞组成性表达的杀念珠菌蛋白复合物。表达钙卫蛋白的上皮细胞似乎形成了菌丝渗透的屏障。在HIV感染期间，钙卫蛋白的表达和向唾液中的释放显著减少，表明粘膜上皮钙卫蛋白的表达受损。在艾滋病中，钙卫蛋白下调，念珠菌病的风险增加。角质形成细胞与感染的未成熟树突状细胞和其他免疫细胞之间的相互作用可能在HIV易位、钙卫蛋白下调和念珠菌病的发生中起重要作用。因此，我们假设，口腔粘膜上皮细胞的HIV感染下调钙卫蛋白，以减少耐念珠菌。为了验证这一假设，我们将1）确定HIV转胞吞作用中口腔粘膜上皮钙卫蛋白的需要; 2）确定HIV摄取到口腔上皮细胞中是否调节钙卫蛋白特异性mRNA的表达; 3）确定树突状细胞或其他免疫细胞在HIV感染期间是否与口腔角质形成细胞合作以下调钙卫蛋白的表达; 4）分析转胞吞前后口腔上皮细胞对念珠菌感染的易感性;和5）确定对念珠菌感染的易感性是否与钙卫蛋白的下调相关。总的来说，这些实验将提出钙卫蛋白保护免受念珠菌感染的基础，先天免疫在艾滋病中如何受阻，并将为在随后的R 01应用中精确定义这些机制奠定基础。

DESCRIPTION (provided by applicant): Calprotectin is a candidacidal protein complex that is constitutively expressed by squamous mucosal epithelial cells. Epithelial cells expressing calprotectin appear to form a barrier to hyphal penetration. During HIV infection the expression and release of calprotectin into saliva is significantly reduced suggesting that expression of mucosal epithelial calprotectin is impaired. In AIDS, calprotectin is down-regulated and the risk of candidiasis increases. Cross talk between keratinocytes and infected immature dendritic and other immune cells are likely to play a significant role in the translocation of HIV, down regulation of calprotectin and the occurrence of candidiasis. We hypothesize, therefore, that HIV infection of oral mucosal epithelial cells down-regulates calprotectin to reduce resistance to Candida. To test this hypothesis, we will 1) determine the requirement of oral mucosal epithelial calprotectin in transcytosis of HIV; 2) determine if uptake of HIV into oral epithelial cells regulates expression of calprotectin-specific mRNA; 3) ascertain if dendritic or other immune cells cooperate with oral keratinocytes during HIV infection to down-regulate expression of calprotectin; 4) analyze oral epithelial cells before and after transcytosis for susceptibility to Candida infection; and 5) determine if susceptibility to Candida infection is associated with down-regulation of calprotectin. Collectively these experiments will suggest the basis for calprotectin protection against Candida infections, how innate immunity is thwarted in AIDS, and will set the stage to precisely define these mechanisms in a subsequent R01 application.