Engineering the immune response for improved resolution of Staphylococcus infecti

描述（由申请方提供）：多形核白细胞（PMN）在针对病原体的先天性免疫应答中至关重要。金黄色葡萄球菌（SA）是最常见的医院感染之一，也是皮肤伤口不愈合的最常见原因。 皮肤伤口中的PMN募集和脓肿形成是这些感染的标志，并且是细菌清除所需的。然而，越来越多的生物膜形成耐药性菌株如耐甲氧西林金黄色葡萄球菌（MRSA）的出现使其治疗复杂化，并造成严重的公共卫生威胁。例如，在2000年至2005年期间，MSRA参与皮肤和软组织感染的比例从4%增加到42%，并且仍然很高。我们实验室发表的数据表明，在皮肤伤口部位对中性粒细胞的炎症反应进行策略性操纵可抑制感染并提高非瘢痕愈合的效率。这些研究采用表达EGFP-PMN的转基因小鼠的非侵入性整体动物荧光成像。这种方法提供了一个实时的多参数读出的动态变化，中性粒细胞的招聘和寿命，SA的负担，伤口闭合。我们建议研究三种不同的机制，这些机制共同作用以募集PMN用于SA感染组织中的宿主防御，包括：（1）PMN从骨髓中的稳健和持续动员，（2）PMN在脓肿内的体内存活时间延长，以及（3）ckit+造血干细胞和祖细胞（HSPC）在伤口内增殖并分化为成熟PMN的运输。支配该提议的中心假设是，可以对PMN和HSPC在脓肿中的募集和功能进行工程化，以优化微生物感染的清除并防止延迟正常组织愈合的异常炎症。翻译目标将是实现水凝胶递送系统，以引导先天免疫应答，用于改善组织损伤小鼠模型中持续性SA感染的分辨率。

DESCRIPTION (provided by applicant): Polymorphonuclear (PMN) leukocytes are critical in the innate immune response against pathogens. Staphylococcus aureus (SA) is among the most common nosocomial infections and the most frequent cause of non-healing skin wounds. PMN recruitment and abscess formation in cutaneous wounds is a hallmark of these infections and is required for bacterial clearance. However, the increasing emergence of biofilm forming antibiotic-resistant strains such as methicillin resistant SA (MRSA) has complicated their treatment and created a serious public health threat. For instance, MSRA involvement in skin and soft tissue infections increased from 4% to 42% between 2000 and 2005 and remains high. Published data from our laboratory indicates that strategic manipulation of the inflammatory response of PMN at the site of a cutaneous wound suppresses infection and improves the efficiency of non-scar healing. These studies employ non- invasive whole animal fluorescence imaging of transgenic mice expressing EGFP-PMN. This methodology provides a real-time multiparameter readout of the dynamic changes in PMN recruitment and lifetime, SA burden, and wound closure. We propose to investigate three distinct mechanisms that act in concert to recruit PMN for host defense in SA infected tissue, including: (1) a robust and sustained mobilization of PMN from the bone marrow, (2) a prolonged in vivo survival of PMN within the abscess, and (3) trafficking of ckit+ hematopoietic stem and progenitor cells (HSPC) that proliferate and differentiate into mature PMN within the wound. The central hypothesis governing this proposal is that PMN and HSPC recruitment and function in the abscess can be engineered to optimize clearance of microbial infections and prevent aberrant inflammation that delays normal tissue healing. A translational goal will be implementation of a hydrogel delivery system to guide the innate immune response for improving resolution of a persistent SA infection in a mouse model of tissue injury.