HSV-1-specific T-cell responses in human sensory ganglia

1 R21 AI 081060 - 01 A1 Koelle，大卫M. HSV-1是一种重要的人类病原体，可引起角膜、视网膜、脑等严重感染 软组织、面部和口腔组织，还导致围产期发病率和死亡率。没有 获得许可的HSV-1疫苗慢性HSV-1感染的位点在感觉神经节的神经元内， 特别是使面部、角膜和脑膜神经衰弱的三叉神经节（TG）。动物模型 HSV-1感染最近证明，TG是一个免疫活性器官， 存在神经节驻留的HSV-1特异性CD 8和CD 4 T细胞，并且这些细胞在功能上是 在外植体和移植系统中很重要。目的：研究HSV-1在慢性期TG患者中的免疫学特征， HSV-1已经与其共同进化了数百万年的天然宿主，本申请关注 对来自匿名人类尸体的组织中对HSV-1的TG免疫应答的影响。长期目标 HSV-1研究计划的主要内容是HSV-1亚单位疫苗的合理设计和 理解抗原加工和呈递给人TG中的HSV-1特异性T细胞。这笔赠款 这代表了对HSV-1免疫学的计划性持续关注的开始。第一个目标是 确定哪些HSV-1表位和抗原被人类中HSV-1特异性CD 8 T细胞识别 HSV-1感染的三叉神经节。我们将使用虚拟HSV-1 ORFeome和人工抗原 在TG组织中的HSV-1-特异性CD 8 T细胞应答。第二个目标是 确定哪些HSV-1表位和抗原被人类中HSV-1特异性CD 4 T细胞识别 TG组织。在供体内含有多个表位的抗原，这些抗原被T细胞识别， 多个供体，并被CD 4和CD 8 T细胞识别，如果检测到这些，将是合理的 HSV-1亚单位或载体疫苗的候选物。

1R21AI081060-01A1 Koelle, David M. HSV-1 is a significant human pathogen, causing serious infections of the cornea, retina, brain parenchyma, and facial and oral tissues, and also causing perinatal morbidity and mortality. There is no licensed vaccine for HSV-1. The locus of chronic HSV-1 infection is within neurons in sensory ganglia, particularly the trigeminal ganglia (TG) that enervate that face, cornea, and meninges. Animal models of HSV-1 infection have recently proven that the TG is an immunocompetent organ with regard to the presence of ganglia-resident, HSV-1-specific CD8 and CD4 T-cells, and that these cells are functionally important in explant and transplant systems. To study chronic phase TG HSV-1 immunology in the natural host that HSV-1 has been co-evolving with for millions of years, the present application focuses on the TG immune response to HSV-1 in tissue from anonymous human cadavers. The long term goals of the HSV-1 research program are the rational design of an HSV-1 subunit vaccine and an understanding of antigen processing and presentation to HSV-1-specific T-cells in human TG. This grant represents the beginning of a planned sustained focus on HSV-1 immunology. The first Aim is to determine which HSV-1 epitopes and antigens are recognized by HSV-1-specific CD8 T-cells in human HSV-1-infected trigeminal ganglia. We will use a virtual HSV-1 ORFeome and artificial antigen presenting cells to dissect the HSV-1-specific CD8 T-cell response in TG tissues. The second Aim is to determine which HSV-1 epitopes and antigens are recognized by HSV-1-specific CD4 T-cells in human TG tissues. Antigens that contain multiple epitopes within-donor, that are recognized by T-cells from multiple donors, and are recognized by both CD4 and CD8 T-cells, if these are detected, will be rational candidates for HSV-1 subunit or vectored vaccines.