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能否成功建立感染方面起着主要作用。这可能对虫媒病毒特别重要，其中包括一些与生物防御相关的和新出现的病原体，因为这些病毒中的许多最初在节肢动物载体接种后在树突状细胞中复制。在初步研究中，当甲型病毒，包括B类生物防御病原体委内瑞拉马脑炎病毒(VEE)在哺乳动物细胞中培养时，这些病毒可以有效地诱导感染的髓系树突状细胞(MDC)产生IIFN反应。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型干扰素反应。此外，初步研究还表明，I型干扰素诱导的这种差异是由于蚊子细胞衍生病毒表面存在高甘露聚糖所致。由于DC-SIGN是一种甘露糖结合的C型凝集素，介导蚊源甲型病毒感染MDCS，它可以抑制Toll样受体(TLRs)对树突状细胞的激活，这表明蚊源病毒可能与DC-SIGN或其他甘露糖结合蛋白相互作用，抑制感染的MDC中干扰素的诱导。此外，这可能使节肢动物传播的甲型病毒在从蚊子媒介传播后，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型病毒在诱导I型干扰素方面的差异，2)确定这种作用是I型干扰素所特有的，还是延伸到受感染的MDCS对其他细胞因子的诱导，以及3)评估病毒糖基化和/或与DC-SIGN的相互作用在介导这一效应中的作用。本申请中概述的研究将为其他研究奠定基础，这些研究旨在：1)表征蚊源病毒避免在受感染的MDCS中诱导抗病毒反应的机制；2)使用小动物模型评估蚊源病毒诱导的干扰素减少是否会影响这些病毒感染和致病的能力。

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.