Role of lymphoid DCs in HSV-1 latency

描述（由申请方提供）：HSV-1感染的标志是在感染个体的神经节中建立潜伏期。在潜伏感染者的生命中，病毒偶尔会重新激活，回到眼睛并引起复发性疾病。事实上，角膜瘢痕形成（CS）（也称为疱疹基质角膜炎（HSK））的主要原因是HSV-1在潜伏期再激活后诱导的瘢痕形成。减少潜伏期以及随后的复发性感染和视力丧失的最有效方法是减少感染小鼠三叉神经节中的潜伏期。我们已经表明，复发性HSV-1感染显着减少免疫小鼠的DC耗竭。CD 11 c + CD 8 <$+ DCs与潜伏期和复发率的增加有关。我们以前的研究支持这样的观点，即将DC群体从CD 11 c + CD 8 <$+转移到CD 11 c + CD 8 <$-DC将减少潜伏感染小鼠中潜伏期的建立和随后的复发。因此，由于与复发性眼部感染相关的问题，预防和/或减少潜伏期的建立应该是针对眼部HSV-1的预防性免疫策略的主要目标。因此，基于我们发表的和初步的研究，我们将使用DC刺激因子来转移DC群体，以减少T细胞耗竭，从而减少眼部感染小鼠的TG中潜伏期的建立/维持。我们建议：目的：检验将DC推向骨髓相关（CD 11 c + CD 8 <$-）和远离淋巴相关（CD 11 c + CD 8 <$+）将通过减少感染小鼠三叉神经节中T细胞耗竭来减少感染小鼠的潜伏期的假设。我们已发表的研究表明，CD 11 c + CD 8 <$+ DCs参与眼部感染小鼠TG潜伏期的增加。此外，我们的初步研究表明，CD 11 c + CD 8 <$+ DCs参与T细胞的耗竭，这种T细胞耗竭参与潜伏期的增加。我们将测试是否：（a）与用GM-CSF和gD处理的小鼠相比，联合施用聚乙二醇化GM-CSF和gD将增强骨髓相关DC，并通过减少T细胞耗竭进一步减少免疫小鼠中的潜伏期;和（B）与聚乙二醇化GM-CSF类似，用激动剂Ab激活光敏素受体（LT <$r）将驱动CD 11 c + CD 8 <$r扩增。- 并减少潜伏感染小鼠的TG中的潜伏期和减少T细胞耗竭。这些研究的结果将确定通过使用免疫刺激剂进一步刺激CD 11 c + CD 8 <$- DCs以提高针对HSV-1潜伏期的DNA免疫效力的重要性。还将表征这些疫苗策略的长期作用，以确定是否引发长寿命的CD 8 + T细胞应答。 公共卫生相关性：HSV感染的标志之一是病毒能够在受感染宿主的神经元中建立潜伏期。我们已经表明，淋巴样DC在感染小鼠三叉神经节潜伏期的建立中起主要作用，并且包含淋巴样DC增加HSV-1潜伏期。我们现在计划通过使用聚乙二醇化的GM-CSF和抗LT受体激动剂将淋巴样DC推向髓样DC来进一步减少感染小鼠三叉神经节中的潜伏期。

DESCRIPTION (provided by applicant): A hallmark of infection with HSV-1 is establishment of latency in ganglia of the infected individual. During the life of the latently infected individual,the virus can occasionally reactivate, travel back to the eye and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) also know as herpes stromal keratitis (HSK) is the scarring induced by HSV-1 following reactivation from latency. The most efficient way to decrease latency and thus subsequent recurrent infections and loss of vision is to reduce latency in trigeminal ganglia of infected mice. We have shown that recurrent HSV-1 infection was reduced significantly by depletion of DCs in immunized mice. The increase of latency and recurrences was associated with CD11c+CD8¿+ DCs. Our previous studies support the concept that shifting the DCs population from CD11c+CD8¿+ to CD11c+CD8¿- DCs will reduce establishment of latency and the subsequent recurrences in latently infected mice. Consequently, because of the problems associated with recurrent ocular infection, preventing and/or reducing establishment of latency should be a major goal of a prophylactic immunization strategy against ocular HSV-1. Thus, based on our published and Preliminary Studies, we will use DCs stimulatory factors to shift the DCs population in order to reduce T cell exhaustion and consequently, the establishment/maintenance of latency in the TGs of ocularly infected mice. We propose to: Aim: Test the hypothesis that pushing DCs toward myeloid-related (CD11c+CD8¿-) and away from lymphoid-related (CD11c+CD8¿+) will reduce latency in infected mice by decreasing T cell exhaustion in trigeminal ganglia of infected mice. Our published studies have shown that CD11c+CD8¿+ DCs are involved in the enhancement of latency in the TGs of ocularly infected mice. In addition, our preliminary studies suggest that CD11c+CD8¿+ DCs are involved in exhaustion of T cells and this T cell exhaustion is involved in the increase of latency. We will test whether: (a) Co-administration of pegylated GM-CSF with gD will enhance myeloid-related DCs and further reduce latency in immunized mice compared with mice that treated with GM- CSF and gD by reducing T cell exhaustion; and (b) Similar to pegylated-GM-CSF, activation of the lymphotoxin ¿ receptor (LT¿r) with an agonist Ab will drive the expansion of CD11c+CD8¿- and reduce latency and decrease T cell exhaustion in TGs of latently infected mice. The results of these studies will determine the importance of further stimulating CD11c+CD8¿- DCs through the use of an immune stimulator to improve the efficacy of DNA immunization against HSV-1 latency. The long-term effects of these vaccine strategies will also be characterized to determine whether long-lived CD8+ T cell responses are elicited. PUBLIC HEALTH RELEVANCE: One of the hallmarks of HSV infection is the ability of the virus to establish latency in neurons of an infected host. We have shown that lymphoid DCs are playing a major role in establishment of latency in trigeminal ganglia of infected mice and inclusion lymphoid DCs increases HSV-1 latency. We now plan to further reduce latency in trigeminal ganglia of infected mice by pushing the lymphoid DCs to myeloid DCs using pegylated-GM-CSF and anti-LT¿R agonist.