Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases.
Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases.
复制标题
通过灭活 Sts 磷酸酶来增强对皮内土拉弗朗西斯菌 LVS 感染的抵抗力。
DOI：
10.1128/iai.00406-17
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发表时间：
2017
影响因子：
3.1
通讯作者：
Carpino,Nick
中科院分区：
文献类型：
--
作者：
Parashar,Kaustubh;Kopping,Erik;Frank,David;Sampath,Vinaya;Thanassi,DavidG;Carpino,Nick
TCR信号转导抑制蛋白（Sts-1和Sts-2）是两种同源的磷酸酶，其负调节包括T淋巴细胞在内的许多造血谱系中的信号转导途径。缺乏Sts表达的小鼠的特征在于增强的T细胞应答。此外，最近的一项研究表明，Sts −/−小鼠对白色念珠菌的全身感染具有深刻的抵抗力，其抵抗力的特点是存活率提高，关键外周器官中的真菌清除更快，以及炎症反应改变。为了研究Sts在细菌病原体感染的主要宿主反应中的作用，我们评估了Sts −/−小鼠对革兰氏阴性细菌病原体感染的反应。土拉热弗朗西丝菌是一种兼性细菌病原体，在多种细胞类型内进行细胞内复制，是土拉菌病的病原体。弗朗西斯菌属感染的特征是免疫反应延迟，随后是强烈的炎症反应，导致广泛的组织损伤和败血性休克。在此，我们证明了缺乏Sts表达的小鼠对F.土拉热。耐药性的特征是高剂量皮内感染后致死率降低，脾脏中细胞因子反应改变，多个外周器官中细菌清除增强。tularensis LVSex vivo，显示出增强的细胞内细菌限制。这些观察结果表明，Sts蛋白在宿主对细菌感染的反应中起着重要的调节作用，并且它们强调了Sts在调节功能相关的免疫反应途径中的作用。
TheSuppressor ofTCRsignaling proteins (Sts-1 and Sts-2) are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic lineages, including T lymphocytes. Mice lacking Sts expression are characterized by enhanced T cell responses. Additionally, a recent study demonstrated thatSts−/−mice are profoundly resistant to systemic infection by Candida albicans, with resistance characterized by enhanced survival, more rapid fungal clearance in key peripheral organs, and an altered inflammatory response. To investigate the role of Sts in the primary host response to infection by a bacterial pathogen, we evaluated the response ofSts−/−mice to infection by a Gram-negative bacterial pathogen. Francisella tularensis is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia. Francisella infections are characterized by a delayed immune response, followed by an intense inflammatory reaction that causes widespread tissue damage and septic shock. Herein, we demonstrate that mice lacking Sts expression are significantly resistant to infection by thelivevaccinestrain (LVS) of F. tularensis. Resistance is characterized by reduced lethality following high-dose intradermal infection, an altered cytokine response in the spleen, and enhanced bacterial clearance in multiple peripheral organs.Sts−/−bone marrow-derived monocytes and neutrophils, infected with F. tularensis LVSex vivo, display enhanced restriction of intracellular bacteria. These observations suggest the Sts proteins play an important regulatory role in the host response to bacterial infection, and they underscore a role for Sts in regulating functionally relevant immune response pathways.