Role of Complement Activation in Severe COVID-19

补体激活在严重 COVID-19 中的作用

基本信息

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
项目类别：
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

项目摘要

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 的小鼠的纤维化过度。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。