Arbovirus Evasion of Type I Interferon Induction

产品说明：病毒与先天免疫系统之间的初始相互作用在决定病毒是否成功建立感染方面起着重要作用。这可能是特别重要的虫媒病毒，其中包括一些生物防御相关的和新兴的病原体，因为这些病毒中的许多最初复制的树突状细胞接种后的节肢动物载体。在初步研究中，当甲病毒，包括委内瑞拉马脑炎病毒（VEE），一种B类生物防御病原体，在哺乳动物细胞中生长时，这些病毒是感染的髓样树突细胞（mDC）中I型IFN应答的强效诱导剂。然而，当这些相同的病毒在蚊子细胞中生长时，它们有效地感染了mDC，但未能在这些细胞中诱导I型IFN应答。此外，初步研究还表明，I型IFN诱导的这种差异是由于蚊子细胞衍生病毒表面上存在高甘露糖聚糖。由于DC-SIGN（一种介导mDC被蚊子来源的甲病毒感染的甘露糖结合C型凝集素）的连接可以抑制Toll样受体（TLR）对树突状细胞的活化，这表明蚊子来源的病毒可以与DC-SIGN或一些其他甘露糖结合蛋白相互作用以抑制感染的mDC中的干扰素诱导。此外，这可以允许节肢动物携带的甲病毒避免在从蚊子载体递送后在最初感染的树突细胞中诱导抗病毒免疫应答，从而增强病毒在脊椎动物宿主中建立感染的能力。为了表征这种潜在的重要免疫逃避途径，我们建议：1）对蚊子和哺乳动物细胞衍生的甲病毒之间关于I型IFN诱导的差异进行详细分析，2）确定这种作用是否特异于I型干扰素或延伸到感染的mDC对其他细胞因子的诱导，和3）评估病毒糖基化和/或与DC-SIGN的相互作用在介导该效应中的作用。本申请中概述的研究将形成设计用于以下的额外研究的基础：1）表征蚊子来源的病毒避免在感染的mDC中诱导抗病毒应答的机制，和2）使用小动物模型来评估蚊子细胞来源的病毒的干扰素诱导的降低是否影响这些病毒建立感染和引起疾病的能力。

DESCRIPTION: The initial interaction between viruses and the innate immune system plays a major role in determining whether the virus will successfully establish infection. This may be particularly important for arboviruses, which include a number of biodefense related and emerging pathogens, since many of these viruses initially replicate in dendritic cells following inoculation by the arthropod vector. In preliminary studies, when alphaviruses, including Venezuelan equine encephalitis virus (VEE), a class B biodefense pathogen, were grown in mammalian cells, these viruses were potent inducers of type IIFN responses in infected myeloid dendritic cells (mDC). However, when these same viruses were grown in mosquito cells, they efficiently infected the mDCs, but failed to induce type I IFN responses in these cells. Furthermore, preliminary studies also indicated that this difference in type I IFN induction was due to the presence of high mannose glycans on the surface of the mosquito cell derived virus. As ligation of DC-SIGN, a mannose binding C-type lectin that mediates infection of mDCs by mosquito-derived alphaviruses, can suppress dendritic cell activation by Toll-like receptors (TLRs), this suggests that the mosquito-derived virus may interact with DC-SIGN or some other mannose binding protein to inhibit, interferon induction in the infected mDC. Furthermore, this may allow arthropod borne alphaviruses to avoid the induction of antiviral immune responses in the initially infected dendritic cell following delivery from the mosquito vector and thereby enhance the virus's ability to establish infection in the vertebrate host. In order to characterize this potentially important pathway of immune evasion, we propose to: 1) Perform a detailed analysis on the differences between mosquito and mammalian cell derived alphaviruses with respect to type I IFN induction, 2) Determine whether this effect is specific to type I interferons or extends to the induction of other cytokines by the infected mDCs, and 3) Evaluate the role of viral glycosylation and/or interactions with DC-SIGN in mediating this effect. The studies outlined in this application will form the basis for additional studies designed to: 1) characterize the mechanism by which mosquito derived viruses avoid the induction of antiviral responses in infected mDCs, and 2) use small animal models to evaluate the whether the decreased interferon induction by mosquito cell derived viruses affects the ability of these viruses to establish infection and cause disease.