SK2b型A族链球菌激活纤溶酶原的分子机制的研究

Activation of human plasminogen (hPg) is a critical step in Group A Streptococcus (GAS) infection. Recently it was found that hPg activators produced by different GAS strains are different, leading to the classification of three types of GAS strains, namely SK1-GAS, SK2a-GAS and SK2b-GAS. The molecular mechanisms of hPg activation by these GAS strains are still unclear. Previously in our study it was shown that the function of hPg activator and hPg receptor in SK2b-GAS could be inhibited by lysine analog, aminocaproic acid (EACA), indicating that lysine-binding function is very important in hPg activation by SK2b-GAS. Here, by investigating the effects of EACA and lysine mutation on the functions of hPg-activation related proteins in SK2b-GAS, we will explore the specific proteins which bind hPg through lysine, and the specific lysines involved in the bindings in hPg-activation pathways, thus to elucidate the molecular mechanisms of hPg-activation by SK2b-GAS and to evaluate the potential of EACA in prevention and treatment of SK2b-GAS infections.

A族链球菌（Group A Streptococcus，GAS）感染的关键是激活宿主纤溶酶原（Human plasminogen，hPg）。根据产生的hPg激活因子的不同，GAS菌株被分为三类，即SK1型，SK2a型和SK2b型。目前这些不同GAS激活hPg的具体分子机制还不十分清楚。我们前期的研究结果显示，赖氨酸类似物ε-氨基己酸（EACA）能够抑制SK2b型GAS中hPg激活因子和受体的功能，暗示赖氨酸结合作用在SK2b型GAS激活hPg中具有重要作用。本项目拟通过研究EACA以及赖氨酸突变对hPg激活相关蛋白的功能的影响，阐明赖氨酸结合作用在SK2b型GAS激活hPg中的重要性，并确定在SK2b型GAS激活hPg途径中，哪些蛋白的相互作用是以赖氨酸结合为基础，以及参与结合的具体赖氨酸，从而揭示SK2b型GAS激活hPg的分子机制，并探讨EACA用于防治SK2b型GAS感染的可能性。

宿主纤溶酶原（Human plasminogen，hPg）的激活是SK2b型A族链球菌（Group A Streptococcus，GAS）感染的关键。前期研究有迹象表明赖氨酸类似物ε-氨基己酸（EACA）对SK2b型SK激活hPg有抑制作用，详细研究EACA以及赖氨酸突变对hPg激活相关蛋白的功能的影响，有助于我们了解SK2b型GAS激活hPg的机制，并评估EACA是否具有防治GAS感染的潜力。本项目通过构建SK2b和Pam蛋白的13个突变体，检测hPg激活，确定了Pam蛋白的类赖氨酸位点在SK2b型GAS激活hPg中起主要作用，从而确定了SK2b型GAS激活hPg的分子机制是通过Pam蛋白的类赖氨酸位点结合hPg，结合后的hPg被SK2b激活。通过检测EACA对SK1和SK2b结合和激活hPg的研究，确定了EACA能够显著抑制Pam和SK2b结合hPg，并显著抑制Pam存在下SK2b对hPg的激活，因此EACA能够抑制Pam的类赖氨酸位点，从而抑制SK2b型GAS激活hPg。基于Pam的类赖氨酸位点在SK2b型GAS中保守存在，推断EACA具有防治GAS侵袭性感染的潜力。本项目的研究结果在了解GAS的致病机制以及防治GAS感染方面具有重要意义。