Protein therapy to treat virus induced cardiopulmonary injury

蛋白质疗法治疗病毒引起的心肺损伤

• 批准号: 10747665
• 负责人: Chuanxi Cai
• 金额: $ 73.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-06 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747665
• 关键词: Protein; therapy; treat; virus; induced

Project Summary The worldwide human population continually faces the challenge of seasonal influenza and other aggressive respiratory virus infections. While the focus of research is usually on pulmonary manifestations, there is emerging evidence that virus-induced “cytokine storm” as well as direct infection of cardiac tissue causes heart dysfunction during influenza and other respiratory virus infections. A therapeutic approach that mitigates virus-induced inflammation and restores cardiopulmonary integrity is urgently needed to treat virus-induced multi-organ injuries. MG53 is a member of the TRIM protein family and plays an essential role in cell membrane repair. We show previously that systemic administration of recombinant human MG53 (rhMG53) protein protects against injuries to the heart and lung in rodent and large animal models. Here we present new data that reveal a vital role for MG53 in cardiopulmonary protection associated with virus infection. In addition to facilitating tissue repair, MG53 also has an anti-inflammatory role in immunity. Human macrophages express MG53 and loss of MG53 leads to increased type I interferon and IL-6 production in virus infection due to hyperactivation of NF-κB. MG53 knockout mice infected with influenza virus display increased tissue inflammation and morbidity even though virus titers are comparable to wild type mice. Intravenous administration of rhMG53 prevents death of wild type mice subjected to a lethal influenza virus challenge, by reducing cytokine storm and preventing tissue damage through inhibition of pyroptosis. These findings establish a new paradigm for treatment of infectious disease and identify MG53 as a new target for control of virus-induced tissue injury. We hypothesize that the dual function of MG53 in tissue-repair and limiting inflammation will combat cardiopulmonary injury caused by influenza virus. We will dissect the roles of MG53 in preserving heart and lung function following influenza virus infection using custom-generated MG53 loss of function and gain of function mouse models. We will elucidate the molecular underpinnings and interplay between MG53 inhibition of both pyroptosis and NF-κB signaling as host-defense mechanisms in the heart and lungs upon exposure to influenza virus. We will further establish the dosing and timing strategies for administration of rhMG53 in mice to establish the prophylactic and therapeutic windows for ameliorating virus-induced multi-organ failure. Since MG53 is not directly antiviral, potential exists for combination therapy of rhMG53 with antivirals to effectively treat virus-induced cardiopulmonary injury. Thus, we will quantify synergistic effects of treating influenza virus-infected mice with rhMG53 and FDA-approved anti- influenza drugs on cardiac and lung viral titers, pathology, and function.

项目摘要 全世界人口持续面临季节性流感和其他侵袭性疾病的挑战。 呼吸道病毒感染虽然研究的重点通常是肺部表现，但正在出现 病毒诱导的“细胞因子风暴”以及心脏组织的直接感染导致心脏功能障碍的证据 流感和其他呼吸道病毒感染。一种减轻病毒诱导的 炎症和恢复心肺完整性是治疗病毒引起的多器官损伤的迫切需要 受伤MG 53是TRIM蛋白家族的成员，在细胞膜修复中起重要作用。我们 先前显示，重组人MG 53（rhMG 53）蛋白全身给药可防止 在啮齿动物和大型动物模型中对心脏和肺的损伤。在这里，我们提出了新的数据，揭示了一个重要的 MG 53在与病毒感染相关的心肺保护中的作用。除了促进组织修复， MG 53在免疫方面也具有抗炎作用。人巨噬细胞表达MG 53和MG 53的缺失 由于NF-κB的过度活化，导致病毒感染中I型干扰素和IL-6的产生增加。MG53 感染流感病毒的基因敲除小鼠显示出增加的组织炎症和发病率， 病毒滴度与野生型小鼠相当。静脉内施用rhMG 53防止野生型死亡 通过减少细胞因子风暴和防止组织损伤， 通过抑制细胞凋亡这些发现为传染病的治疗建立了一个新的范例， 鉴定MG 53作为控制病毒诱导组织损伤的新靶标。我们假设的双重功能 MG 53在组织修复和限制炎症方面将对抗流感病毒引起的心肺损伤。 我们将使用以下方法来剖析MG 53在流感病毒感染后保护心肺功能中的作用： 定制生成的MG 53功能丧失和功能获得小鼠模型。我们将阐明 MG 53抑制细胞凋亡和NF-κB信号传导作为宿主防御的基础和相互作用 心脏和肺中的机制暴露于流感病毒。我们将进一步确定剂量， 在小鼠中给予rhMG 53的时间策略，以建立以下疾病的预防和治疗窗口： 改善病毒引起的多器官衰竭。由于MG 53不是直接抗病毒的，因此存在潜在的抗病毒性。 rhMG 53与抗病毒药物的联合治疗有效治疗病毒诱导的心肺损伤。因此我们 将量化用rhMG 53和FDA批准的抗- 流感药物对心脏和肺病毒滴度、病理学和功能的影响。