HIV Modulates Oral Mucosal Calprotectin and Candidiasis

描述(由申请人提供)： 钙保护素是一种念珠菌活性蛋白复合体，由鳞状黏膜上皮细胞结构性表达。表达钙保护素的上皮细胞似乎形成了菌丝穿透的屏障。在HIV感染过程中，唾液中钙保护素的表达和释放明显减少，提示粘膜上皮钙保护素的表达受到损害。在艾滋病中，钙保护素表达下调，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、钙保护素下调和念珠菌病的发生中发挥重要作用。因此，我们假设，口腔粘膜上皮细胞感染HIV下调了钙保护素的表达，从而减少了对念珠菌的耐药性。为了验证这一假说，我们将1)确定艾滋病毒跨细胞作用对口腔粘膜上皮细胞钙保护素的需求；2)确定口腔上皮细胞对艾滋病毒的摄取是否调节钙保护素特异性mRNA的表达；3)确定树突状细胞或其他免疫细胞在艾滋病毒感染期间是否与口腔角质形成细胞合作下调钙保护素的表达；4)分析口腔黏膜上皮细胞在跨细胞作用前后对念珠菌感染的易感性；以及5)确定对念珠菌感染的易感性是否与钙保护素下调有关。总而言之，这些实验将建议钙保护素预防念珠菌感染的基础，以及先天免疫在艾滋病中是如何受挫的，并将为在随后的R01应用中准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.