Targeting matrix metalloproteinases to limit immunopathology in airborne infectio

描述(申请人提供)：空气传播的病原体导致肺部发炎，并在人与人之间传播。此外，免疫介导的组织损伤会导致发病率、器官衰竭和死亡。基质金属蛋白酶(MMPs)由于其独特的降解肺细胞外基质结构成分的能力，在这一免疫病理过程中起着核心作用。最近，我们已经证明MMPs是人类结核病(TB)组织损伤的关键驱动因素(Elkington J Clin Invest 2011)。已经开发了几种用于其他炎症条件的基质金属蛋白酶抑制剂，并已证明在人类身上是安全的。基质金属蛋白酶的抑制可能代表了一种新的辅助治疗方法，可以缩短感染持续时间，降低人类气传呼吸道感染的死亡率。假设：在人类空气传播感染中，基质金属蛋白酶活性导致基质破坏、病原体传播和呼吸衰竭。目的：通过研究两种具有不同病理机制的全球重要病原体：(I)导致肺基质慢性破坏的结核分枝杆菌和(Ii)促使基质快速重塑和传播的流感，来研究抑制基质金属蛋白酶作为空气传播传染病的宿主靶向治疗。我们将通过体外人类细胞模型和体内基质金属蛋白酶人源化小鼠的研究，确定基质金属蛋白酶在结核病中的作用，并研究抑制基质金属蛋白酶以改善患者预后的治疗效果。人类结核肉芽肿的体外模型将利用生物电喷雾技术来制造三维浸入结核的球体，以研究基质金属蛋白酶抑制剂。我们将研究分枝杆菌感染在人源化的小鼠中的病理学，以确定在体内对基质金属蛋白酶的活性和抑制的影响。我们将研究甲型流感对上皮细胞、单核细胞和巨噬细胞中基质金属蛋白酶的上调作用。将使用雪貂流感感染模型来研究体内的基质金属蛋白酶抑制活性及其减少免疫介导的组织损伤的能力。摘要：本研究确定了可限制空气传播感染的病理以降低发病率、传播率和死亡率的基质金属蛋白酶抑制剂。这些结果不仅与结核病和大流行性流感有关，而且还与其他迅速致命的空气传播感染(例如SARS冠状病毒)有关。我们将建立一种新的治疗模式，针对宿主过度的基质金属蛋白酶活性，以改善肺部感染的预后。 公共卫生相关性：空气传播感染是对世界人口的主要健康威胁，大流行性流感和多药耐药药物都有可能迅速传播。病原体推动细胞外基质的破坏，以促进其分裂，并导致发病率和死亡率。基质金属蛋白酶在免疫介导的组织损伤中起着关键作用。本项目研究基质金属蛋白酶抑制作为一种新的治疗方法，以减少空气感染的发病率和死亡率。

DESCRIPTION (provided by applicant): Airborne pathogens drive lung inflammation and are transmitted from person to person. Furthermore, immune-mediated tissue damage causes morbidity, organ failure and death. Matrix metalloproteinases (MMPs) have a central role in this immunopathology due to their unique ability to degrade the structural components of the lung extracellular matrix. Recently, we have demonstrated that MMPs are critical drivers of tissue damage in human tuberculosis (TB) (Elkington J Clin Invest 2011). Several MMP inhibitors have been developed for other inflammatory conditions and have a proven safety record in man. MMP inhibition may represent a novel adjunctive therapy to shorten the duration of infectivity, and reduce mortality from human airborne respiratory infections. Hypothesis: MMP activity drives matrix destruction, pathogen dissemination and respiratory failure in human airborne infection. Aims: to investigate MMP inhibition as host-targeted therapy for airborne infectious disease by studying two globally important pathogens with contrasting pathologies: (i) Mycobacterium tuberculosis which causes chronic destruction of the lung matrix, and (ii) Influenza which drives rapid matrix remodeling and transmission. We will define the role of MMPs in TB and investigate the therapeutic effects of MMP inhibition to improve patient outcomes by studying in vitro human cellular models and in vivo MMP humanized mice. In vitro models of human TB granulomas will be developed using a bio-electrospray technology to produce 3-dimensional TB-impregnated spheroids to study MMP inhibitors. We will investigate the pathology of mycobacterial infection in MMP-1 humanized mice to define the effects of MMP activity and inhibition in vivo. We will study MMP upregulation by influenza A in epithelial cells monocytes and macrophages. A ferret model of influenza infection will be used to study MMP inhibitory activity in vivo and its ability to reduce immune-mediated tissue damage. Summary: This research identifies MMP inhibitors that limit pathology of airborne infection to reduce morbidity, transmission and mortality. The results are relevant not only to TB and pandemic influenza, but also to other rapidly fatal airborne infections (e.g., SARS coronavirus). We will establish a new therapeutic paradigm targeting excessive host MMP activity to improve outcomes in pulmonary infection. PUBLIC HEALTH RELEVANCE: Airborne infection is a primary health threat to the world population, and there is a potential for rapid spread of both pandemic influenza and multidrug resistant agents. Pathogens drive destruction of the extracellular matrix to facilitate their sprea and cause morbidity and mortality. Matrix metalloproteinases have a critical role in immune-mediated tissue damage. This project investigates matrix metalloproteinase inhibition as a new therapeutic approach to reduce morbidity and mortality from airborne infection.