Arbovirus Evasion of Type I Interferon Induction

描述：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。这可能对虫媒病毒尤其重要，虫媒病毒包括许多生物防御相关病原体和新出现的病原体，因为许多病毒在节肢动物载体接种后最初在树突状细胞中复制。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，这些病毒在受感染的髓样树突状细胞（mDC）中是IIFN型反应的有效诱导剂。然而，当这些病毒在蚊子细胞中生长时，它们有效地感染了mDCs，但未能在这些细胞中诱导I型IFN反应。此外，初步研究还表明，这种I型IFN诱导的差异是由于蚊子细胞衍生病毒表面存在高甘露糖聚糖。DC-SIGN是一种结合甘露糖的c型凝集素，可介导蚊源性甲病毒对mDC的感染，连接DC-SIGN可抑制toll样受体（TLRs）对树突状细胞的激活，这表明蚊源性病毒可能与DC-SIGN或其他甘露糖结合蛋白相互作用，抑制被感染mDC的干扰素诱导。此外，这可能允许节肢动物传播的甲病毒在蚊子载体传递后避免在最初感染的树突状细胞中诱导抗病毒免疫反应，从而增强病毒在脊椎动物宿主中建立感染的能力。为了描述这一潜在的重要免疫逃避途径，我们建议：1)详细分析蚊子和哺乳动物细胞来源的甲病毒在I型干扰素诱导方面的差异，2)确定这种作用是仅针对I型干扰素还是扩展到被感染的mDCs诱导其他细胞因子，以及3)评估病毒糖基化和/或与DC-SIGN相互作用在介导这种作用中的作用。本申请中概述的研究将成为进一步研究的基础，旨在：1)描述蚊子衍生病毒避免在感染的mDCs中诱导抗病毒反应的机制，2)使用小动物模型评估蚊子细胞衍生病毒诱导干扰素减少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.