Innate Immunity and Herpes Simplex Pathogenesis

描述(申请人提供)：单纯疱疹病毒1型(HSV-1)是一种复杂的DNA病毒，在世界大多数人口中导致终身感染。在大多数人中，这种疾病的特征是原发病，包括喉咙痛，然后是多年来的无症状携带者，偶尔会出现局部反应，通常会出现“发烧水泡”。该病毒在潜伏期携带在神经元中，可能会导致脑炎。另一方面，新生儿则呈现出非常不同的临床图景，其特征要么是局部疾病，要么是脑炎，要么是高死亡率的播散性感染。我们实验室最近的工作表明，HSV通过与TLR2相互作用诱导炎性细胞因子的产生。同样的病毒也通过TLR9诱导干扰素的产生。HSV刺激TLR的机制将通过病毒遗传学和分离蛋白的表达来研究。利用转基因细胞和基因敲除小鼠，我们计划定义引起HSV诱导的细胞因子和干扰素的途径，并确定TLRs如何影响HSV的免疫反应(使用动物模型)和再激活疾病的发展(在人类中)。

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) is a complex DNA virus that causes life long infection in the majority of the world's population. In most people the disease is characterized by a primary illness that includes a sore throat and is variably followed by many years of asymptomatic carriage punctuated by occasional local reactions, usually occurring as "fever blisters." The virus is carried in its latent phase in neurons and may cause encephalitis. Newborn babies, on the other hand, present with a much different clinical picture that is characterized by either localized disease, encephalitis, or disseminated infection with a high mortality. Recent work in our laboratory has demonstrated that HSV induces the production of inflammatory cytokines through its interaction with TLR2. The same viruses also induce the production of interferon through TLR9. The mechanism by which HSV stimulates TLRs will be investigated using viral genetics and expression of isolated proteins. Using transfected cells and knockout mice we plan to define the pathways responsible for HSV induced cytokines and interferon and determine how TLRs affect both the immune response to HSV (using animal models), and the development of reactivation disease (in humans).