Neisserial Porins and Antigen Presenting Cells

描述(由申请人提供)：NeisSerial Porins(淋球菌蛋白I[PIA或PIB]或脑膜炎球菌1类[PorA]、2或3[PorB]蛋白)是NeisSerial外膜的主要蛋白质成分。它们在结构和功能上与其他革兰氏阴性菌有显著的同源性。这些孔蛋白已被证明是有效的免疫佐剂，我们已经证明这与它们激活抗原提呈细胞(APC)并上调共刺激分子CD86和II类MHC的表达有关。在这个提议的最后一个周期中，我们已经证明了孔蛋白，特别是PorB对APC的这种作用是通过模式识别受体TLR2对PorB的识别而介导的，并且是MyD88和TIRAP依赖的。本研究的目的有三个方面，1)证实Porin PorB与TLR2的直接相互作用，2)确定哪个TLR2辅助受体、TLR1或TLR6参与PorB诱导的TLR2介导的活性，以及3)确定哪些APC对Porin佐剂活性是必需的，以及这种活性与APC抗原提呈和TLR2激活的关系。这些目标的实现将极大地提高我们对细菌成分与TLRs的相互作用以及TLRs和APC在免疫反应中的作用的了解。

DESCRIPTION (provided by applicant): Neisserial porins (gonococcal Protein I [PIA or PIB] or meningococcal class 1 [PorA], 2 or 3 [PorB] proteins) are the major protein constituent of the Neisserial outer membrane. They have significant homology in structure and function amongst themselves and other Gram-negative porins. These porins have been shown to be potent immune adjuvants and we have demonstrated that this related to their ability to activate antigen presenting cells (APC), and upregulate the expression of the costimulatory molecule CD86 and class II MHC. During the last cycle of this proposal, we have shown that this effect of porins, specifically PorB, on APC is mediated by recognition of PorB by the pattern recognition receptor TLR2 and is MyD88 and TIRAP dependent. The goals of this current proposal are three-fold, 1) Demonstrate the direct interaction of porin PorB with TLR2, 2) determine which TLR2 co-receptor, TLR1 or TLR6 is involved in PorB induced TLR2 mediated activity and 3) determine which APC are essential for porin adjuvant activity and the relationship of this activity to APC antigen presentation and TLR2 activation. The fulfillment of these aims will greatly enhance our knowledge regarding bacterial component interaction with TLRs and the role of TLRs and APC in immune responses.