SSA The Role of Innate Cell PTP1b in Susceptibility to Infection

免疫系统是维持健康的关键组成部分。随着人口年龄的增长，由于免疫系统的生理和形态功能的改变及其适应性(免疫衰老)的丧失，他们变得更容易受到感染。近年来，威胁生命的感染急剧上升，这是由于更多的老龄人口以及用于抗击老年性疾病的治疗方法。这一新出现的危机促使人们越来越需要更好地了解控制对感染、自然健康和衰老的保护性免疫反应的分子机制。老年人对感染的免疫反应减弱尤其与单核细胞和巨噬细胞功能不全有关。对感染的先天反应的一个基本组成部分涉及巨噬细胞识别病原体细胞壁成分，并通过吞噬、细胞因子/ROS产生、抗菌肽和激活适应性免疫反应3吞噬和摧毁细胞。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这些机制如何随着年龄的变化仍然不清楚。基于我们令人兴奋的新发现，我们提出PTP1B是巨噬细胞功能的主要调节因子，并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，包括去磷酸化和失活胰岛素受体的能力，并调节JAK/STAT免疫介导的反应。PTP1B与衰老过程中与肥胖相关的炎症和胰岛素抵抗的发生有关。PTP1B已经是治疗年龄相关性糖尿病和肥胖症以及HER2阳性乳腺癌的有效靶点，抑制剂目前正在进行第二阶段临床试验。然而，这些新疗法如何影响感染的易感性还没有文献记载。我们已经证明，在用TLR4激动剂激活时，PTP1B限制了巨噬细胞中抗炎IL-10的产生和信号传递，并且髓系PTP1B缺陷小鼠受到保护，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，我们现在发现，PTP1B的丢失，特别是在髓系细胞(LysM PTP1B-/-)中，显著改变了这些小鼠对系统性真菌感染(白色念珠菌)模型的敏感性，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着重要作用。利用我们成熟的体内感染模型和新的尖端技术，本研究的目的是探索这一假说，并全面表征巨噬细胞和PTP1B缺陷小鼠对细菌(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学反应。我们的目标是：1.在年轻和老年激活的人和小鼠巨噬细胞中，确定PTP1B对白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PTP1B在感染白念珠菌和金黄色葡萄球菌感染巨噬细胞时所控制的特定细胞内信号通路。根据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，描述髓系特异性PTP1B基因敲除动物对全身真菌感染的免疫反应。

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.