MAPK phosphatases and innate immunity

说明书(申请人提供)：丝裂原活化蛋白激酶(MAPK)信号通路在调节宿主对感染的先天免疫反应中起着不可或缺的作用。这些信号通路的调节由丝裂原激活的蛋白磷酸酶(MAPs)严格控制，以确保对感染的适当水平的反应。例如，个别哺乳动物MAP表达受损的小鼠表现出免疫反应调节的丧失，导致严重的炎症和败血症，以应对感染。我的实验室和其他人最近的工作导致了一类新的细菌效应物的发现，包括志贺氏菌、OSPF和沙门氏菌MkfI，它们是细菌图谱。我们有初步数据表明，OSPF和MkfI在感染过程中以不同的方式失活MAPK信号级联。OSPF选择性地去磷酸化ERK和p38MAPK，而MkfI去磷酸化ERK、p38和SAP/JNK。在这些观察的基础上，我们假设细菌通过选择性地灭活MAPK信号通路来差异地调节宿主的先天免疫反应，并且这种差异信号导致宿主细胞细胞因子的分泌改变。此外，我们假设小分子对细菌图谱的抑制将为通过增强宿主天然免疫反应而发挥作用的抗菌剂的开发提供新的途径。尽管本提案中的以下实验集中在OSPF MAP家族上，但这些研究可能会对其他细菌病原体调节宿主天然免疫的机制产生重要的见解，这些细菌病原体也会使宿主MAPK信号通路失活，包括耶尔森氏菌和炭疽杆菌。与公共卫生相关：许多细菌病原体，如志贺氏菌，都会注射蛋白质来解除宿主的免疫反应。该提案将研究其中一种蛋白质OSPF用来抑制宿主先天免疫反应的机制。该提案还将调查抑制OSPF的药物是否可能通过增强宿主自身的免疫反应来提供一种治疗感染的新方法。

DESCRIPTION (provided by applicant): Mitogen activated protein kinase (MAPK) signaling cascades play an integral role in mediating the host innate immune response to infection. Regulation of these signaling pathways is tightly controlled by mitogen activated protein phosphatases (MAPs) that ensure appropriate levels of response to infection. For example, mice impaired in expression of individual mammalian MAPs exhibit loss of regulation of immune responses resulting in severe inflammation and sepsis in response to infections. Recent work from my laboratory and others has resulted in the discovery of a novel class of bacterial effectors including Shigella OspF and Salmonella MkfI that are bacterial MAPs. We have preliminary data that OspF and MkfI differentially inactivate MAPK signaling cascades during infections. OspF selectively dephosphorylates ERK and p38 MAPK while MkfI dephosphorylates ERK, p38 and SAP/JNK. Based on these observations we hypothesize that bacterial pathogens differentially modulate the host innate immune response by selectively inactivating MAPK signaling cascades and that this differential signaling results in alterations in the secretion of host cell cytokines. Furthermore we hypothesize that inhibition of bacterial MAPs by small molecules will provide new avenues for the development of antimicrobial agents that act by boosting the host innate immune response. Although the following experiments in this proposal are focused on the OspF family of MAPs, these studies will likely result in important insights into the mechanisms of regulation of host innate immunity by other bacterial pathogens that also inactivate host MAPK signaling pathways including Yersinia species and Bacillus anthracis. PUBLIC HEALTH RELEVANCE: Many bacterial pathogens like Shigella inject proteins that disarm the host immune response. This proposal will investigate the mechanism used by one of these proteins, OspF, to suppress the host innate immune response. The proposal will also investigate whether drugs that inhibit OspF might provide a new way to treat infections by boosting the hosts own immune response.