MAPK phosphatases and innate immunity

描述（由申请人提供）：丝裂原活化蛋白激酶（MAPK）信号级联在介导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是由丝裂原活化蛋白磷酸酶（MAPs）严格控制的，它确保了对感染的适当反应水平。例如，个体哺乳动物MAPs表达受损的小鼠表现出免疫反应调节的丧失，导致感染反应中的严重炎症和败血症。我的实验室和其他人最近的工作导致发现了一类新的细菌效应物，包括志贺氏菌OspF和沙门氏菌MkfI，它们都是细菌map。我们有初步数据表明，在感染期间，OspF和MkfI不同地灭活了MAPK信号级联。OspF选择性地去磷酸化ERK和p38 MAPK，而MkfI去磷酸化ERK、p38和SAP/JNK。基于这些观察结果，我们假设细菌病原体通过选择性地失活MAPK信号级联来调节宿主先天免疫反应，并且这种差异信号导致宿主细胞因子分泌的改变。此外，我们假设小分子抑制细菌MAPs将为开发通过增强宿主先天免疫反应起作用的抗菌药物提供新的途径。尽管本提案中的后续实验主要集中在OspF的map家族，但这些研究可能会对其他细菌病原体调控宿主先天免疫的机制产生重要的见解，这些细菌病原体也会灭活宿主MAPK信号通路，包括耶尔森菌和炭疽杆菌。公共卫生相关性：许多细菌性病原体，如志贺氏菌，注入的蛋白质可以解除宿主的免疫反应。本研究将探讨其中一种蛋白OspF抑制宿主先天免疫反应的机制。该提案还将研究抑制OspF的药物是否可以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.