SSA The Role of Innate Cell PTP1b in Susceptibility to Infection

免疫系统是维持健康的重要组成部分。随着人口老龄化，由于免疫系统生理和形态功能的变化及其适应性的丧失（免疫衰老），他们变得更容易受到感染。近年来，危及生命的感染急剧上升，这是由于老年人口增加以及用于对抗年龄引起的疾病的治疗方法。这种新出现的危机使人们越来越需要更好地了解控制对感染的保护性免疫反应的分子机制，自然地在健康和衰老中。随着年龄的增长，对感染的免疫反应减弱与单核细胞和巨噬细胞的功能不足有关。对感染的先天反应的一个重要组成部分包括巨噬细胞识别病原体细胞壁成分，并通过吞噬作用、细胞因子/ROS的产生、抗菌肽和适应性免疫反应的激活来吞噬和破坏细胞。宿主免疫细胞表达模式识别受体，感知病原体相关分子模式（PAMPs）。然而，控制下游细胞信号机制的确切分子和途径，以及它们如何随着年龄而改变，仍不清楚。基于这些令人兴奋的新发现，我们提出PTP1B是巨噬细胞功能的主要调节因子，可以指导感染诱导的转录反应的输出。PTP1B是一种丰富的、广泛表达的非受体蛋白酪氨酸磷酸酶，它调节重要的信号通路，包括去磷酸化和灭活胰岛素受体的能力，以及调节Jak/STAT免疫介导的反应。PTP1B与衰老过程中肥胖相关的炎症和胰岛素抵抗的发展有关。PTP1B已经是年龄相关性糖尿病和肥胖以及her2阳性乳腺癌的有效治疗靶点，抑制剂目前处于II期临床试验中。然而，这些新疗法如何影响对感染的易感性还没有文献记载。我们已经证明，在TLR4激动剂的激活下，PTP1B限制了巨噬细胞中抗炎IL-10的产生和信号传导，并且髓系PTP1B缺陷小鼠免受饮食和年龄诱导的肥胖和胰岛素抵抗4。在初步研究中，我们发现PTP1B的缺失，特别是髓系细胞（LysM PTP1B-/-）的缺失，显著改变了这些小鼠对全身性真菌感染模型（白色念珠菌）的易感性，并且这些小鼠的巨噬细胞对感染表现出异常的炎症反应。因此，这些数据表明，PTP1B在调节感染的免疫反应中起重要作用。利用我们完善的体内感染模型和新的尖端技术，该研究的目的是探索这一假设，并充分表征巨噬细胞和缺乏PTP1B的小鼠对细菌（金黄色葡萄球菌）和真菌（白色念珠菌）感染模型的细胞和免疫反应。我们的目标是：1。测定在年轻和年老活化的人和小鼠巨噬细胞中，PTP1B对白色念珠菌和金黄色葡萄球菌感染的细胞反应（包括摄取和细胞因子产生）的影响。明确巨噬细胞感染白色念珠菌和金黄色葡萄球菌时，PTP1B控制的特异性细胞内信号通路。描述骨髓特异性PTP1B敲除动物对全身真菌感染的免疫反应，包括对细胞和细胞因子炎症活动的影响，以及衰老对这些过程的影响。

The immune system is a critical component for maintaining health. As the population ages they become more susceptible to infections due to changes in physiological and morphological functions of the immune system and the loss of its adaptability (immunosenescence). Life-threatening infections have risen sharply in recent years, owing to the greater aged population as well as therapeutics used to combat age-induced disorders. This emerging crisis has created the growing need to better understand the molecular mechanisms controlling protective immune responses to infection, naturally in health, and in aging. The diminished immunological response to infection in ageing is especially related to a functional insufficiency of monocytes and macrophages. An essential component of the innate response to infection involves macrophages recognising pathogen cell wall components and engulfing and destroying cells through phagocytosis, cytokine/ROS production, antimicrobial peptides and activation of adaptive immune responses3. Host immune cells express pattern recognition receptors that sense the pathogen-associated molecular patterns (PAMPs). However, the exact molecules and pathways controlling downstream cell signalling mechanisms and how these can be altered with age, are still unclear. Based on our exciting new findings, we propose PTP1B as a major regulator of macrophage function and can direct the output of transcriptional responses induced by infection. PTP1B is an abundant, widely-expressed non-receptor protein tyrosine phosphatase that modulates important signalling pathways including an ability to dephosphorylate and inactivate the insulin receptor and regulate Jak/STAT immune mediated responses. PTP1B is implicated in the development of inflammation and insulin resistance associated with obesity during aging. PTP1B is already a validated therapeutic target for age-associated diabetes and obesity, as well as HER2-positive breast cancer, and inhibitors are currently in Phase II clinical trials. However, how these new therapeutics could influence susceptibility to infection has not been documented. We have shown that, on activation with TLR4 agonists, PTP1B limits anti-inflammatory IL-10 production and signaling in macrophages and that myeloid PTP1B-deficient mice are protected against diet and age-induced obesity and insulin-resistance4. In preliminary studies we have now found that loss of PTP1B, specifically in myeloid cells (LysM PTP1B-/-), significantly alters the susceptibility of these mice to a model of systemic fungal infection (Candida albicans) and that macrophages from these mice demonstrate abnormal inflammatory responses to infection. These data therefore indicate that PTP1B plays an important role in regulation of immune responses to infection.Taking advantage of our well-established in vivo infection models and novel cutting edge technologies, the aim of the studentship is explore this hypothesis and to fully characterise cellular and immunological responses to models of bacterial (Staphylococcus aureus) and fungal (Candida albicans) infection in both macrophages and in mice deficient in PTP1B. Our objectives are to:1. Determine, in young and aged activated human and murine macrophages, the influence of PTP1B on cellular responses to C. albicans and S. aureus infection (including uptake and cytokine production).2. Define the specific intracellular signalling pathways that are controlled by PTP1B on infection of macrophages with C. albicans and S. aureus.3. Characterise the immunological response to systemic fungal infection in myeloid specific PTP1B knockout animals in terms of effects on cellular and cytokine inflammatory activities, and the effect of aging on these processes.