Innate Recognition of Human Herpesviruses

人类疱疹病毒8型(HHV8)，又称卡波西肉瘤相关疱疹病毒(KSHV)和人类疱疹病毒(HHV6)，是疱疹病毒家族的成员，被列入NIAID新出现/再出现病原体名单。在人类中，HHV8/KSHV与三种不同的癌症有关，包括卡波西肉瘤(KS)、原发渗出性淋巴瘤和多中心Castleman病。在撒哈拉以南非洲，KS是男性最常见的癌症。人类疱疹病毒6型(HHV-6)是婴幼儿红疹的感染原因。针对RFA-AI-12-048，“病毒控制的免疫机制，我们建议确定宿主免疫系统如何感知DNA疱疹病毒。我们建议确定多个病原体识别受体(PRRs)与这些DNA病毒的相互作用，以及这些病毒被宿主PRRs感知以激活天然免疫反应的机制。我们推测，参与病毒基因组核酸传感的PRRs能够检测到KSHV和HHV6，并激活先天免疫反应。此外，疱疹病毒感染引起的DNA损伤反应也可能有助于激活先天免疫途径。该项目通过使用尖端的定量蛋白质组学方法来确定病原体感知的新范式转换途径，识别由人类PRR结合的核酸，并确定宿主对NIAID新出现/重新出现的病毒的反应中多个PRR之间的串扰，从而推进了该计划的总体目标。

Human Herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV) and human herpesvirus (HHV6) are members ofthe herpesvirus family and are included on the NIAID list of Emerging/Re-Emerging pathogens. HHV8/KSHV is associated with three different cancers in the human population including Kaposi's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. In Sub-Saharan Africa, KS is the most common cancer in men. Human herpesvirus type-6 (HHV-6) is the infectious cause of roseola infantum in young children. In response to RFA-AI-12-048, "Immune mechanisms of Viral Control, we propose to determine how DNA herpes viruses are sensed by the host immune system. We propose to determine the interaction of multiple pathogen recognition receptors (PRRs) with these DNA viruses and the mechanisms by which these viruses are sensed by host PRRs to activate the innate immune response. We hypothesize that PRRs involved in nucleic acid sensing of viral genomes are able to detect KSHV and HHV6 and activate innate immune responses. Additionally, the DNA damage response induced by herpes viral infection may also contribute to activation of innate immune pathways. This project advances the overall goals of the program by using cutting edge quantitative proteomic approaches to identify novel paradigm shifting pathways of pathogen sensing, identifying nucleic acid binding by human PRRs, and determining cross-talk between multiple PRRs in the host response to NIAID Emerging/Reemerging viruses.