Activation of innate antiviral defenses by LTbetaR

LTbetaR 激活先天抗病毒防御

• 批准号: 6814338
• 负责人: CHRISTOPHER A BENEDICT
• 金额: $ 28.01万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814338
• 关键词: Bunyaviridae; Rift Valley fever virus; bioassay; biological signal transduction; bioterrorism /chemical warfare; cytokine receptors; enzyme linked immunosorbent assay; genetically modified animals; host organism interaction; immune response; immunity; immunopathology; immunoregulation; influenza; interferon alpha; interferon beta; laboratory mouse; polymerase chain reaction; tissue /cell culture; transfection; tumor necrosis factor beta; virus infection mechanism; virus protein

Signaling by the lymphotoxin (LT)/LT-beta receptor (LTIbetaR) cytokine system is required for the development and organization of lymphoid tissue. More recently, LTbetaR signaling has been shown to be critical for innate immune defense to cytomegalovirus infection (CMV). CMV has evolved mechanisms to block the induction of type I interferon (IFNalphabeta), and signaling by the LTbetaR can circumvent this block. Similar to CMV, influenza and several Bunyaviruses also inhibit production of IFNalphabeta, a function performed by their respective nonstructural (NS) proteins. We will assess the contribution of the LTbetaR in regulating innate host-defenses to influenza by utilizing mouse models genetically-deficient or pharmacologically-inhibited for signaling by the LT/LTbetaR cytokine system. Analysis of an influenza mutant lacking NS1 in these models will allow us to further dissect the relationship between LTbetaR signaling, induction of IFNalphabeta and control of influenza pathogenesis. In addition, agonistic anti-LTbetaR antibody will be tested for its ability to restore or enhance antiviral immunity in vivo. Rift Valley fever virus (RVFV) and La Crosse virus (LACV) (members of the Bunyaviridae family) both encode NSs proteins that inhibit the induction of IFNalphabeta, and variants of RVFV containing deletions in NSs are severely attenuated. The ability of LTbetaR signaling to circumvent NSs antagonism of IFNalphabeta will be examined in a tissue culture model where NSs of RVFV and LACV is expressed in the absence of viral infection. Together these approaches will yield valuable information regarding the importance of the LT/LTbetaR cytokine system in regulating innate immune responses to various biodefense category A-C pathogens, and should provide clues as to whether modulation of this pathway may be therapeutically beneficial.

淋巴毒素（LT）/LT-β受体（Ltibetar）细胞因子系统的信号传导是淋巴组织的开发和组织所必需的。最近，LTBETAR信号传导已被证明对于对巨细胞病毒感染（CMV）的先天免疫防御至关重要。 CMV具有阻止I型干扰素诱导（Ifnalphabeta）的发展机制，而LTBETAR的信号传导可以避免此块。与CMV相似，流感和几种Bunyavirus还抑制了Ifnalphabeta的产生，这是由它们各自的非结构（NS）蛋白执行的功能。我们将通过利用LT/LTBETAR细胞因子系统的遗传缺陷或药理抑制的小鼠模型来评估LTBETAR在调节先天宿主防御对流感的贡献。在这些模型中对缺乏NS1的流感突变体的分析将使我们能够进一步剖析LTBETAR信号传导之间的关系，诱导Ifnalphabeta和对流感发病机理的控制。此外，激动剂抗LTBETAR抗体的恢复或增强体内抗病毒免疫的能力将进行测试。 Rift Valley Fever病毒（RVFV）和La Crosse病毒（LACV）（Bunyaviridae家族的成员）均编码NSS蛋白，这些NSS蛋白抑制了ifnalphabeta的诱导，以及NSS中含有RVFV的变体的变体。在组织培养模型中，将检查LTBETAR信号传导规避IFNALPHABETA的NSS拮抗作用的能力，其中在没有病毒感染的情况下表达RVFV和LACV的NSS。这些方法将共同产生有关LT/LTBETAR细胞因子系统在调节对各种生物脱落类别A-C病原体的先天免疫反应中的重要性的有价值的信息，并应提供有关该途径调节的线索 治疗上有益。