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Effect of SARS-CoV-2 on host metabolism and its influence on innate and adaptive immunity

SARS-CoV-2对宿主代谢的影响及其对先天性和适应性免疫的影响

基本信息

批准号：
10927941
负责人：
Catharine Bosio
金额：
$ 11.27万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927941
关键词：
2019-nCoV Age Animals Cause of Death Cell physiology Cells Cessation of life Child Communicable Diseases Data Development Disease Disease Progression Elements Environment Flow Cytometry Generations Genomics Goals Human Imaging technology Immune Immune response Immunity In Vitro Infection Inflammation Inflammatory Response Innate Immune Response Lipids Location Long COVID Lower Respiratory Tract Infection Lung Lung infections Mediator Metabolic Metabolic Pathway Metabolism Modeling Mus Natural Immunity Obesity Organ Pathogenesis Pathway interactions Peripheral Persons Pharmaceutical Preparations Phenotype Population Primary Infection Production Resolution Respiratory Tract Infections Role SARS-CoV-2 immunity SARS-CoV-2 infection Sampling Symptoms T-Lymphocyte Techniques Telemetry Therapeutic Therapeutic Intervention Tissues Vaccination Vaccines Virion Virus adaptive immune response adaptive immunity animal imaging cell type comorbidity diet-induced obesity early phase clinical trial experience in vivo insight lipid mediator lipidomics lung pathogen metabolomics model development mouse model multiple omics new therapeutic target novel therapeutics novel vaccines pandemic disease pathogen post SARS-CoV-2 infection prevent pulmonary function secondary infection temporal measurement

项目摘要

Pulmonary infections represent 5 of the 30 most common causes of death around the world, with lower respiratory infections resulting on average of 4 million deaths each year and the leading cause of death among children under the age of 5. We are currently in the midst of a pandemic caused by the pulmonary pathogen SARS-CoV-2. To date, the number of infections and deaths have surpassed other more typical respiratory infections with over 200 million cases and 4.25 million deaths. Since this is a new virus, there is very little we understand about all facets of the disease (COVID-19) it causes. The IPP section has over a decade of experience dissecting the innate and adaptive immune responses to pulmonary pathogens. Thus, in this project we leverage that experience to define unique features of both innate and adaptive immune responses to this virus with a special emphasis on the metabolic and lipidomic perturbations occurring during sub-lethal and lethal disease. Specific Aim 1: Identify the lipid signatures associated with mild, moderate and severe disease in humans. Lipids and lipid mediators are important molecules for initiating and maintaining inflammatory responses as well as resolving inflammation post-infection. Fortunately, many of these mediators are either targetable with established therapeutics and with drugs that are undergoing early clinical trials. Thus, identification of lipid mediators that are correlated with progression or resolution of SARS-CoV-2 infection provides new therapeutic targets. In FY2021 we identified that obesity was a strong comorbidity for SARS-CoV-2 infection. Moreover we identified that severe infections in the obese host was correlated with lack of production of key lipid mediators. We have extended these studies using a diet induced obesity mouse model in k18-hACE2 mice to more thoroughly interrogate the role of lipid mediators and obesity in infection. Specific Aim 2: Characterize the metabolic shifts in the host that are associated with sub-lethal and lethal SARS-CoV-2 infections in mice Specific shifts in metabolism are critical for mounting effective innate and adaptive immune responses. Using other models of infection we have found that pathogens can influence the ability of the host to properly regulate these shifts. Further, different tissues have differing abilities to mobilize metabolic pathways which also impacts disease progression and resolution. Using a variety of in vivo and in vitro techniques including but not limited to live animal imaging, assessment of metabolites and lipids from target and peripheral tissues, flow cytometry and assessment of metabolic flux in vitro we will determine how SARS-CoV-2 infection alters host metabolism to cause disease. Additionally, we will determine which pathways and mediators are required to resolve infection. By overlaying these results with those we obtain from human samples we will identify new targets for therapeutic intervention for SARS-CoV-2. Specific Aim 3: Identify the role of resident versus circulating T cells in protection against SARS-CoV-2 infection in mice. Generation and retention of T cells in the lung following sub-lethal infection or vaccination is essential for development of effective, long lasting immunity. Currently, there is no data concerning the presence or absence of resident T cells directed against SARS-CoV-2 among hosts that have either resolved infection or received a vaccine. We have determined that sublethal infection results in development of a population of resident T cells in the lung, but that these cells are not sufficient to confer immunity in the nave host. We will also characterize the phenotype and function of these cells to determine why T cells generated following a natural infection cannot provide protective immune responses on their own. Specific Aim 4: Long COVID is an increasing problem for people recovering from SARS-CoV-2 infection. Little is understood about this multi symptom condition. We are developing a model of Long COVID with specific emphasis on the lung and lung function following resolution of a sub-lethal SARS-CoV-2 infection in the mouse model. We will gain insight into how this virus compromises the lung environment long after clearance of infectious virions. We have initiated development of model of long COVID in the k18-hACE2 mouse model and are utilizing our expertise in other infectious diseases and models of pulmonary insult to determine how prior SARS-CoV-2 infection compromises lung function. Telemetry will also be employed to gain real time measurements of pulmonary function following infection.

肺部感染占全球 30 种最常见死因中的 5 种，下呼吸道感染每年平均导致 400 万人死亡，是 5 岁以下儿童死亡的主要原因。我们目前正处于由肺部病原体 SARS-CoV-2 引起的大流行之中。迄今为止，感染和死亡人数已超过其他更典型的呼吸道感染，病例数超过 2 亿，死亡人数 425 万人。由于这是一种新病毒，我们对其引起的疾病 (COVID-19) 的各个方面知之甚少。 IPP 部门在剖析针对肺部病原体的先天性和适应性免疫反应方面拥有十多年的经验。因此，在这个项目中，我们利用这一经验来定义对该病毒的先天性和适应性免疫反应的独特特征，特别强调亚致死和致死疾病期间发生的代谢和脂质组学扰动。具体目标 1：确定与人类轻度、中度和重度疾病相关的脂质特征。脂质和脂质介质是启动和维持炎症反应以及解决感染后炎症的重要分子。幸运的是，许多这些介质要么可以通过现有的疗法或正在进行早期临床试验的药物来靶向。因此，鉴定与 SARS-CoV-2 感染进展或消退相关的脂质介质提供了新的治疗靶点。 2021 财年，我们发现肥胖是 SARS-CoV-2 感染的一个严重合并症。此外，我们发现肥胖宿主的严重感染与关键脂质介质产生的缺乏有关。我们在 k18-hACE2 小鼠中使用饮食诱导的肥胖小鼠模型扩展了这些研究，以更彻底地探讨脂质介质和肥胖在感染中的作用。具体目标 2：表征与小鼠亚致死和致死 SARS-CoV-2 感染相关的宿主代谢变化新陈代谢的特定变化对于产生有效的先天和适应性免疫反应至关重要。使用其他感染模型，我们发现病原体可以影响宿主正确调节这些变化的能力。此外，不同的组织具有不同的调动代谢途径的能力，这也会影响疾病的进展和解决。利用各种体内和体外技术，包括但不限于活体动物成像、目标组织和外周组织的代谢物和脂质评估、流式细胞术和体外代谢流评估，我们将确定 SARS-CoV-2 感染如何改变宿主代谢从而导致疾病。此外，我们将确定解决感染所需的途径和介质。通过将这些结果与我们从人类样本中获得的结果叠加，我们将确定 SARS-CoV-2 治疗干预的新靶点。具体目标 3：确定驻留 T 细胞与循环 T 细胞在预防小鼠 SARS-CoV-2 感染方面的作用。亚致死感染或疫苗接种后，T 细胞在肺部的产生和保留对于形成有效、持久的免疫力至关重要。目前，尚无关于已解决感染或接受疫苗的宿主中是否存在针对 SARS-CoV-2 的常驻 T 细胞的数据。我们已经确定，亚致死感染会导致肺部产生一群常驻 T 细胞，但这些细胞不足以赋予原始宿主免疫力。我们还将表征这些细胞的表型和功能，以确定为什么自然感染后产生的 T 细胞不能自行提供保护性免疫反应。具体目标 4：对于从 SARS-CoV-2 感染中恢复的人们来说，长期新冠肺炎是一个日益严重的问题。人们对这种多症状病症知之甚少。我们正在开发一种长新冠肺炎模型，在小鼠模型中解决亚致死性 SARS-CoV-2 感染后，重点关注肺和肺功能。我们将深入了解这种病毒在感染性病毒粒子清除后很长时间内如何损害肺部环境。我们已开始在 k18-hACE2 小鼠模型中开发长 COVID 模型，并利用我们在其他传染病和肺部损伤模型方面的专业知识来确定先前的 SARS-CoV-2 感染如何损害肺功能。遥测技术还将用于实时测量感染后的肺功能。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice.

DOI：
10.1172/jci.insight.155896
发表时间：
2022-01-25
期刊：
JCI insight
影响因子：
8
作者：
Jessop F;Schwarz B;Scott D;Roberts LM;Bohrnsen E;Hoidal JR;Bosio CM
通讯作者：
Bosio CM

Cutting Edge: Lung-Resident T Cells Elicited by SARS-CoV-2 Do Not Mediate Protection against Secondary Infection.

DOI：
10.4049/jimmunol.2100608
发表时间：
2021-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Roberts LM;Jessop F;Wehrly TD;Bosio CM
通讯作者：
Bosio CM

Effective inhibition of HCoV-OC43 and SARS-CoV-2 by phytochemicals in vitro and in vivo.

DOI：
10.1016/j.ijantimicag.2023.106893
发表时间：
2023-09
期刊：
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
影响因子：
10.8
作者：
Ojha, Durbadal;Jessop, Forrest;Bosio, Catharine M.;Peterson, Karin E.
通讯作者：
Peterson, Karin E.

Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model.

DOI：
10.1038/s41467-021-22580-8
发表时间：
2021-04-16
期刊：
Nature communications
影响因子：
16.6
作者：
Rosenke K;Hansen F;Schwarz B;Feldmann F;Haddock E;Rosenke R;Barbian K;Meade-White K;Okumura A;Leventhal S;Hawman DW;Ricotta E;Bosio CM;Martens C;Saturday G;Feldmann H;Jarvis MA
通讯作者：
Jarvis MA

Targeting 2-Oxoglutarate-Dependent Dioxygenases Promotes Metabolic Reprogramming That Protects against Lethal SARS-CoV-2 Infection in the K18-hACE2 Transgenic Mouse Model.