MOLECULAR ANALYSIS OF NEUTROPHIL ACTIVATION BY CHEMOATTRACTANTS

该项目的最初目标是确定白细胞如何迁移到感染和炎症部位。我们发现，一大类特定的细胞表面受体统称为趋化受体调节这一过程。后来我们发现，这些受体的一部分被包括艾滋病毒在内的各种微生物病原体用来感染细胞并导致疾病。在过去的一年里，我们发表了新的证据，扩大了特定的化学吸引受体在炎症和感染中的已知作用。关于艾滋病，我们发表了以下新发现：1.HIV可以利用CX3CR1感染试管中的细胞，CX3CR1是两个基因决定的变体，与不同的HIV感染易感性和疾病进展相关，这表明该受体是人群中HIV疾病的重要调节因子，因此它可能是一个有用的药物靶点。2.)主要HIV受体CCR5的基因变异CCR5D32影响患者对高效抗逆转录病毒疗法的临床反应，这对识别最有可能对该疗法有反应的个体具有意义。3.)一种调节化学诱导剂RANTES的产生的基因变体，通过CCR5发挥作用，与艾滋病毒传播风险的变化相关，这表明RANTES模拟可能在治疗方面有效。4.)在Hana Golding小组发起的合作工作中，我们发现受体CCR8表达在胸腺细胞上，在胸腺细胞上可以促进HIV感染，这可能对理解HIV导致免疫缺陷的机制有重要意义。5.)在KT Jeang的团队发起的一项合作中，我们展示了HIV蛋白TAT作为化学吸引物受体和HIV受体CXCR4的特异性拮抗剂的功能，并提出了TAT调节HIV疾病进展速度的机制。在我们的炎症研究方面，我们发现了细菌多肽趋化物质的第二种小鼠受体亚型，并提出了一种机制，通过这两种亚型作为信号转接器，促进吞噬细胞从血液到细菌感染部位的移动。我们还定义了额外的小鼠受体，通过特定的化学诱导剂介导白细胞的激活，这将使我们能够在动物模型中研究这些受体的生物学作用。

The original aim of this project was to define how white blood cells migrate to sites of infection and inflammation. We found that a large family of specific cell surface receptors known collectively as chemoattractant receptors regulates this process. Later we found that a subset of these receptors is used by various microbial pathogens, including HIV, to infect cells and cause disease. In the past year we published new evidence expanding the known roles of specific chemoattractant receptors in inflammation and infection. With regard to AIDS, we published the following new findings: 1.) CX3CR1, which HIV can use to infect cells in the test tube, exists as two genetically determined variants which correlate with different susceptibility to HIV infection and disease progression, suggesting that this receptor is an important regulator of HIV disease in populations, and therefore that it may be a useful drug target. 2.)The genetic variant CCR5D32 of the major HIV receptor CCR5 affects the clinical response of patients to highly active anti-retroviral therapy, which has implications for identifying individuals most likely to respond to this therapy. 3.) A genetic variant that regulates the production of the chemoattractant RANTES, which acts via CCR5, correlates with altered risk of HIV transmission, suggesting that RANTES mimics could be effective therapeutically. 4.)In collaborative work initiated by Hana Golding's group, we found that the receptor CCR8 is expressed on thymus cells where it can facilitate HIV infection, which may be important for understanding the mechanism of immunodeficiency caused by HIV. 5.) In a collaboration initiated by KT Jeang's group, we showed that the HIV protein tat functions as an antagonist specific for the chemoattractant receptor and HIV receptor CXCR4, and proposed a mechanism by which tat could regulate the rate of HIV disease progression. With regard to our inflammation studies, we identified a second subtype of mouse receptor for a bacterial peptide chemoattractant and proposed a mechanism by which the two subtypes act as a signaling relay to facilitate movement of phagocytic cells from the blood to sites of bacterial infection. We also defined additional mouse receptors that mediate activation of white blood cells by specific chemoattractants, which will allow us to study the biological role of these receptors in an animal model.