Mpeg1 in Innate Immunity

描述（由申请人提供）：在本修订申请中，我们表明穿孔蛋白-2（Mpeg 1）缺陷小鼠无法清除鼠伤寒沙门氏菌的口胃感染和耐甲氧西林金黄色葡萄球菌（MRSA）的表皮感染。野生型、穿孔蛋白-2足够的同窝仔清除两种类型的细菌。这些发现支持了我们先前的体外数据，这些数据表明穿孔蛋白-2对于清除细胞内细菌感染是必不可少的。 穿孔蛋白-2在源自内胚层、外胚层、神经外胚层和间充质细胞的所有细胞中普遍表达：组成型或可由IFN诱导。我们的数据还表明，杀死细胞内的细菌是造成细菌感染中观察到的炎症反应的原因，也是细菌清除所必需的。我们在炎症性肠病的葡聚糖硫酸钠模型中的新数据表明，P-2负责引起炎症反应，为IBD的发病机制提供了新的见解，这对于开发克罗恩病的治疗方案可能很重要。此外，P-2在抗菌防御中的作用为针对抗生素耐药性细菌感染的药物开发提供了机会。在本申请中，我们将在三个具体目标上开展工作。在第一个目标中，我们将研究粘膜免疫P-2充足和P-2缺乏小鼠口胃感染沙门氏菌和确定的作用和分子机制的炎症反应与P-2。在第二个具体目标中，我们将研究P-2在葡聚糖硫酸钠（DSS）疾病模型中诱导腹泻的作用以及P-2在微生物组组成中的作用。 在第三个具体目标中，将研究P-2缺陷小鼠对耐甲氧西林金黄色葡萄球菌（MRSA）的易感性，并研究P-2介导的角质形成细胞中MRSA的杀伤的分子机制。

DESCRIPTION (provided by applicant): In this revised application we show that Perforin-2 (Mpeg1) deficient mice are unable to clear orogastric infection with Salmonella typhimurium and epicutaneous infection with methicillin resistant Staphylococcus aureus (MRSA). Wild type, Perforin-2 sufficient littermates clear both types of bacteria. These findings support our previous in vitro data that showed that Perforin-2 is essential for clearing intracellular bacterial infections. Perforin-2 is expressed ubiquitously: constitutive or inducible by IFNs in all cells derived from endodermal, ectodermal, neuroectodermal and mesenchymal cells. Our data also suggest that killing of bacteria inside cells is responsible fo the inflammatory response observed in bacterial infections and required for bacterial clearance. Our new data in the dextran sodium sulfate model of inflammatory bowel disease suggest that P-2 is responsible for causing the inflammatory response providing novel insights into the pathogenesis of IBD which may be important for developing treatment options for Crohn's disease. In addition, the role of P-2 for anti-bacterial defense provides opportunities for drug development against antibiotic resistant bacterial infections. In ths application we will pursue work in three specific aims. In the first aim we will study mucosal immunity in P-2 sufficient and P-2 deficient mice to orogastric infection with Salmonela typhimurium and determine the role and molecular mechanisms of the inflammatory response in relation to P-2. In the second specific aim we will study the role of P-2 in the induction of diarrhea in the disease model of dextran sodium sulfate (DSS) and the role of P-2 in the composition of the microbiome. In the third specific aim, the susceptibility of P-2 deficint mice to methicillin resistant Staphylococcus aureus (MRSA) will be investigated and the molecular mechanism of P-2 mediated killing of MRSA in keratinocytes studied.