BifA Triggers Phosphorylation of Ezrin to Benefit Streptococcus equi subsp. zooepidemicus Survival from Neutrophils Killing.
BifA Triggers Phosphorylation of Ezrin to Benefit Streptococcus equi subsp. zooepidemicus Survival from Neutrophils Killing.
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DOI：
10.3390/biomedicines10050932
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发表时间：
2022-04-19
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
马链球菌动物寄生虫（SEZ）ATCC 35246可侵入脑并在脑组织中引起严重的嗜中性粒细胞浸润。这种微生物可以在压力中性粒细胞浸润情况下存活并繁殖至极高的CFU负荷（108-109/器官）。本研究的目的是探索SEZ高毒力毒株通过其特异性bifA基因避免被大脑中的中性粒细胞清除的机制。我们分离了原代小鼠中性粒细胞来治疗SEZ WT和bifA基因缺陷型（ΔBif）菌株。ΔBif株在体外抗中性粒细胞杀伤的能力减弱。通过co-IP和免疫印迹鉴定中性粒细胞中BifA和ezrin蛋白之间的相互作用。在中性粒细胞中，BifA与ezrin相互作用并以PKC依赖的方式触发ezrin在其Thr 567位点的磷酸化，然后磷酸化ezrin的过度升高招募Dbl并激活Rac 1。由于Rac 1与几种关键的细胞功能密切相关，其异常激活将导致中性粒细胞功能障碍，并从中性粒细胞杀伤中受益于SEZ存活。我们的研究结果揭示了BifA和ERM家族蛋白（用于ezrin，radixin，moesin）相互作用的新结果，这发生在中性粒细胞中的BifA和ezrin之间，并有助于大脑中的SEZ存活。BifA应被视为预防SEZ感染的药物开发的潜在靶点。
Streptococcus equi subsp. zooepidemicus (SEZ) ATCC35246 can invade the brain and cause severe neutrophils infiltration in brain tissue. This microorganism can survive and reproduce to an extremely high CFU burden (108–109/organ) under stressful neutrophils infiltration circumstances. The aim of this research is to explore the mechanism of the SEZ hypervirulent strain with its specific bifA gene which avoids being eliminated by neutrophils in the brain. We isolated the primary mouse neutrophils to treat SEZ WT and bifA gene defective (ΔBif) strains. The ΔBif strain had a weakened function of defending against neutrophils killing in vitro. The interaction between BifA and ezrin proteins in neutrophils were identified by co-IP and immunoblot. In neutrophils, the BifA interacts with ezrin and triggers the phosphorylation of ezrin at its Thr567 site in a PKC-dependent manner, then the excessive elevation of phosphorylated-ezrin recruits Dbl and activates Rac1. Since the Rac1 is closely relevant to several critical cellular functions, its abnormal activation will lead to neutrophils dysfunction and benefit to SEZ survival from neutrophils killing. Our findings reveal a novel consequence of BifA and ERM family protein (for ezrin, radixin, moesin) interaction, which happens between BifA and ezrin in neutrophils and contributes to SEZ survival in the brain. BifA should be considered as a potential target for drug development to prevent SEZ infection.
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