Novel Mouse Model Reveals That Serine Phosphorylation of L-Plastin Is Essential for Effective Splenic Clearance of Pneumococcus.
Novel Mouse Model Reveals That Serine Phosphorylation of L-Plastin Is Essential for Effective Splenic Clearance of Pneumococcus.
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DOI：
10.4049/jimmunol.2000899
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发表时间：
2021-05-01
期刊：
影响因子：
--
通讯作者：
Morley SC
中科院分区：
文献类型：
--
作者：
Anaya EP;Lin X;Todd EM;Szasz TP;Morley SC
无脾会导致对有荚膜细菌（例如肺炎球菌）危及生命的败血症的易感性。然而，脾环境中预防肺炎球菌菌血症的细胞成分尚未确定。遗传性 LPL 缺陷小鼠模型揭示，肌动蛋白捆绑蛋白 L-plastin (LPL) 对于边缘区 B 细胞的生成和抗肺炎球菌宿主防御至关重要。在独立研究中，LPL 残基 5 (S5) 的丝氨酸磷酸化被描述为调节 LPL 肌动蛋白结合和随后的细胞运动的关键“开关”，尽管许多数据是相关的。为了测试 S5 磷酸化在 LPL 功能中的重要性，并专门评估 LPL S5 磷酸化在抗肺炎球菌宿主防御中的需求，我们生成了“S5A”小鼠，表达内源性 LPL，在该位置具有丝氨酸到丙氨酸的突变。 S5A 小鼠被培育成纯合性，LPL 的表达水平与 WT 相当，但不存在 S5 磷酸化。 S5A 小鼠在静脉注射攻击后，肺炎球菌的清除表现出特定的损害，与 WT 或完全缺乏 LPL 的动物相比，攻击后 24 小时的细菌血流负荷高出 10 倍。血流清除缺陷与边缘区巨噬细胞数量减少以及多种先天免疫细胞吞噬能力降低相关。 S5A 小鼠中其他测试白细胞谱系的发育和功能均正常，例如 T 细胞和 B 细胞运动和激活。因此，S5A 小鼠提供了一种新的系统，可以阐明特定宿主：病原体防御相互作用中关键免疫细胞功能的精确分子控制。
Asplenia imparts susceptibility to life-threatening sepsis with encapsulated bacteria, such as the pneumococcus. However, the cellular components within the splenic environment that guard against pneumococcal bacteremia have not been defined. The actin-bundling protein L-plastin (LPL) is essential for generation of marginal zone B cells and for anti-pneumococcal host defense, as revealed by a mouse model of genetic LPL deficiency. In independent studies, serine phosphorylation of LPL at residue 5 (S5) has been described as a key “switch” in regulating LPL actin-binding and subsequent cell motility, although much of the data are correlative. To test the importance of S5 phosphorylation in LPL function, and to specifically assess the requirement of LPL S5 phosphorylation in anti-pneumococcal host defense, we generated the “S5A” mouse – expressing endogenous LPL bearing a serine-to-alanine mutation at this position. S5A mice were bred to homozygosity and LPL was expressed at levels equivalent to WT, but S5 phosphorylation was absent. S5A mice exhibited specific impairment in clearance of pneumococci following intravenous challenge, with 10-fold higher bacterial bloodstream burden 24 h after challenge compared to WT or fully LPL-deficient animals. Defective bloodstream clearance correlated with diminished population of marginal zone macrophages and with reduced phagocytic capacity of multiple innate immune cells. Development and function of other tested leukocyte lineages were normal in S5A mice, such as T and B cell motility and activation. The S5A mouse thus provides a novel system in which to elucidate the precise molecular control of critical immune cell functions in specific host:pathogen defense interactions.
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影响因子：
8.7
作者：
Morley SC
通讯作者：
Morley SC
DOI：
10.1073/pnas.0307124101
发表时间：
2004-01-06
影响因子：
11.1
作者：
Kang, YS;Kim, JY;Park, CG
通讯作者：
Park, CG
影响因子：
32.4
作者：
Chen, H;Mocsai, A;Brown, EJ
通讯作者：
Brown, EJ
影响因子：
2.8
作者：
Lammers, Adriana J.;de Porto, Alexander P.;van der Poll, Tom
通讯作者：
van der Poll, Tom
影响因子：
4.8
作者：
Jones, SL;Brown, EJ
通讯作者：
Brown, EJ