Role of Complement Activation in Severe COVID-19

补体激活在严重 COVID-19 中的作用

• 批准号: 10765317
• 负责人: Xuebin Qin
• 金额: $ 18.66万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10765317
• 关键词: 2019-nCoV; Antiviral Response; Attenuated; Blood; Body Weight decreased; COVID-19; COVID-19 mortality; COVID-19 pathogenesis; Chemicals; Clinical Research; Complement; Complement Activation; Complement Inactivators; Data; Development; Diet; Dietary Supplementation; Disease; Dose; Epithelial Cells; Fibrosis; Fostering; Genes; Human; Inflammation; Inflammatory Response; Influenza; Injury; Innate Immune Response; Interferons; K-18 conjugate; Keratin; Long COVID; Lung; Modality; Molecular; Morbidity - disease rate; Mus; N-3 polyunsaturated fatty acid; Nutritional; Omega-3 Fatty Acids; Polyunsaturated Fatty Acids; Proliferating; Proteins; Pulmonary Fibrosis; Research; Role; SARS-CoV-2 infection; Structure; System; Testing; Therapeutic; Tissues; assault; cytokine; improved; influenza infection; influenzavirus; lipid mediator; lung injury; lung regeneration; mortality; mouse model; response; severe COVID-19; tissue repair; tool

PROJECT ABSTRACT We recently developed sub-lethal lethal mouse model of Covid-19 (K18-hACE2). We infected these mice with influenza virus or sublethal SARS-CoV-2 infected K18-hACE2 mice to study pathobiology of Covid-mild 19 disease and to identify treatment modalities for long Covid. These studies revealed that both influenza and sub-lethal dose of SARS-CoV-2 causes transients weight loss and damage lung epithelial cells as expected. However, influenza induced inflammation was resolved by proliferation of basal lung epithelial cells organized into pod structure and lung regeneration while sub-lethal SARS-CoV-2 induced inflammation resulted in lung fibrosis. At the molecular level influenza infection induced expression of Keratin genes (Krt5, 15, 16) at dramatically higher levels compared to sub-lethal dose of SARS-CoV-2, consistent with tissue repair in lungs of influenza but fibrosis in the lungs of sub-lethal SARS-CoV-2 infected mice. Importantly, influenza induced much stronger interferon response while SARS-CoV-2 induced much stronger cytokine response, complement response, and fibrosis. These data indicate that a more robust innate immune response, attenuated cytokine and complement response, and activation of pro-resolving molecules may help reduce the mortality and morbidity of SARS-CoV- 2. Omega 3 polyunsaturated fatty acids (n-3 PUFAs) fulfil these criteria because they activate direct anti-viral response proteins and are the precursors of the pro-resolving lipid mediators that favor tissue repair. Indeed, n-3 PUFAs reduce lung fibrosis induced by various chemical and environmental assaults. In this supplemental proposal we will feed sub-lethal SARS-CoV-2 infected mice with n-3 PUFA or n-6 PUFA (control) supplemented diets to test the hypothesis that n-3 PUFAs will improve innate immune response to SARS-CoV-2 infection by moderating the initial injury as determined by weight loss and initial lung injury. We hypothesis further that by increasing tissue and blood concentration of pro-resolving lipid mediators, n-3 PUFAs will promote tissue repair over fibrosis in mice infected with sub-lethal dose of SARS-CoV-2. If these studies are successful they will open a path for human clinical studies aimed at using n-3 PUFAs as nutritional substances to reduce morbidity of long Covid, either alone or in combination with other agents such as complement inhibitors.

项目摘要 我们最近开发了 Covid-19 的亚致死致死小鼠模型（K18-hACE2）。我们感染了 这些感染流感病毒的小鼠或亚致死的 SARS-CoV-2 感染的 K18-hACE2 小鼠进行研究 Covid-mild 19 疾病的病理学，并确定长期 Covid 的治疗方式。这些 研究表明，流感和亚致死剂量的 SARS-CoV-2 都会导致体重瞬时变化 正如预期的那样，肺上皮细胞损失和损伤。然而，流感引起的炎症 通过组织成豆荚结构和肺的基底肺上皮细胞的增殖来解决 再生，而亚致死的 SARS-CoV-2 诱导的炎症导致肺纤维化。在 分子水平流感感染诱导角蛋白基因（Krt5、15、16）表达 与 SARS-CoV-2 的亚致死剂量相比，其水平显着更高，与组织一致 流感病毒的肺部出现修复，但亚致死性 SARS-CoV-2 感染小鼠的肺部出现纤维化。 重要的是，流感诱导了更强的干扰素反应，而 SARS-CoV-2 则诱导了更强的干扰素反应。 更强的细胞因子反应、补体反应和纤维化。这些数据表明 更强大的先天免疫反应，减弱的细胞因子和补体反应，以及 激活促分解分子可能有助于降低 SARS-CoV 的死亡率和发病率 2. Omega 3 多不饱和脂肪酸 (n-3 PUFA) 满足这些标准，因为它们可以激活 直接抗病毒反应蛋白，是促溶解脂质介质的前体， 有利于组织修复。事实上，n-3 PUFA 可以减少由各种化学物质和药物引起的肺纤维化。 环境攻击。 在本补充提案中，我们将用 n-3 喂养亚致死的 SARS-CoV-2 感染小鼠 PUFA 或 n-6 PUFA（对照）补充饮食，以检验 n-3 PUFA 的假设 通过减轻初始损伤来改善对 SARS-CoV-2 感染的先天免疫反应 由体重减轻和初始肺损伤决定。我们进一步假设通过增加组织 和促溶解脂质介质的血液浓度，n-3 PUFA 将促进组织修复 感染亚致死剂量 SARS-CoV-2 的小鼠体内纤维化过度。如果这些研究成功 他们将为人类临床研究开辟一条道路，旨在使用 n-3 PUFA 作为营养品 单独或与其他药物联合使用可降低长期新冠病毒发病率的物质 如补体抑制剂。