MODULATION OF INNATE IMMUNE RESPONSES BY CYTOMEGALOVIRUS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 免疫系统最终无法从宿主中消除巨细胞病毒（CMV）可能是由于复杂的病毒感染。 靶向宿主免疫系统的许多方面的逃避机制。在这个项目中，我们将努力更好地了解 CMV调节先天性免疫应答诱导的分子机制，特别是干扰素应答。具体目标1是确定HCMV如何激活干扰素调节因子3（IRF 3）。这一目标已经完成，结果已经公布。 具体目的2和3：确定人和恒河猴CMV如何干扰干扰素刺激基因（ISG）的IRF 3依赖性转录诱导。 我们已经测试了我们最初的假设，即被膜蛋白pp 65和pp 71负责通过产生缺失病毒来抑制RhCMV对IRF 3的激活。然而，由于这些病毒仍然抑制IRF 3激活，我们现在假设RhCMV含有额外的IRF 3抑制基因。目前的实验旨在识别这些基因。此外，我们现在探索的抑制IFN依赖性ISG诱导RhCMV和我们已经产生的证据表明，HCMV也抑制IRF 3激活。 在本申请的竞争性补充中，我们将研究缺乏pp 65和pp 71的RhCMV是否能够在恒河猴中进行原发和再感染。这是一项新的资助，但代表了对母基金（RO 1 AI 070890）的竞争性补充，以研究RhCMV pp 65在体内的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ultimate inability of the immune system to eliminate cytomegalovirus (CMV) from the host is likely due to sophisticated viral evasion mechanisms that target many aspects of the host immune system. In this project, we will try to gain a better understanding of the molecular mechanisms by which CMV modulates the induction of innate immune responses, particularly the interferon response. Specific aim 1 is to identify how HCMV activates interferon-regulatory factor 3 (IRF3). This aim has been completed and the results have been published. Specific Aims 2 and 3: are to determine how human and rhesus CMV interfere with IRF3-dependent transcriptional induction of interferon-stimulated genes (ISGs). We have tested our original hypothesis that the tegument proteins pp65 and pp71 are responsible for inhibiting IRF3 activation by RhCMV by generating deletion viruses. However, since these viruses still inhibit IRF3 activation, we now hypothesize that RhCMV contains additional IRF3 inhibitory genes. Current experiments are aimed at identifying these genes. In addition, we now explore the inhibition of IFN-dependent ISG induction by RhCMV and we have generated evidence that HCMV also inhibits IRF3 activation. In a competitive supplement to this application, we will examine whether RhCMV lacking pp65 and pp71 is capable of primary and re-infection in rhesus macaques. This is a new grant, but represents a competitive supplement to parent grant (RO1 AI070890) to study the role of RhCMV pp65 in vivo.