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 全球人口不断面临季节性影响力和其他侵略性的挑战 呼吸道病毒感染。虽然研究的重点通常放在肺部表现上，但出现了 病毒引起的“细胞因子风暴”以及心脏组织的直接感染的证据引起心脏功能障碍 在影响力和其他呼吸道病毒感染期间。一种减轻病毒诱导的治疗方法 迫切需要炎症和恢复心肺完整性来治疗病毒诱导的多器官 受伤。 MG53是Trim蛋白家族的成员，在细胞膜修复中起着至关重要的作用。我们 以前证明了重组人MG53（RHMG53）蛋白的系统性给药可预防 啮齿动物和大型动物模型中的心脏和肺部受伤。在这里，我们提供了揭示至关重要的新数据 MG53在与病毒感染相关的心肺保护中的作用。除了促进组织修复外 MG53在免疫中也具有抗炎作用。人类巨噬细胞表达MG53和MG53的损失 由于NF-κB的过度激活，导致病毒感染中的I型干扰素和IL-6产生增加。 MG53 感染受影响力病毒的敲除小鼠表现出增加的组织感染和发病率 病毒滴度与野生型小鼠相媲美。 RHMG53的静脉内给药可防止野生型死亡 通过减少细胞因子风暴并防止组织损伤受到致命影响病毒挑战的小鼠 通过抑制凋亡。这些发现为治疗传染病和 将MG53识别为控制病毒诱导的组织损伤的新目标。我们假设 组织修复中的MG53和限制炎症将打击由影响力病毒引起的心肺损伤。 我们将剖析MG53在使用影响力感染后MG53在保存心脏和肺功能中的作用 自定义生成的MG53功能丧失和功能鼠标模型的增益。我们将阐明分子 Mg53抑制凋亡和NF-κB信号传导的基础和相互作用作为宿主防御 暴露于影响病毒时，心脏中的机制和肺部的机制。我们将进一步建立剂量和 在小鼠中施用RHMG53的计时策略，以建立预防性和治疗窗口 改善病毒诱导的多器官衰竭。由于MG53不是直接抗病毒，因此存在 RHMG53与抗病毒药的联合疗法有效治疗病毒诱导的心肺损伤。那，我们 将量化用RHMG53和FDA批准的抗 - 心脏和肺病毒滴度，病理学和功能的流感药物。