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

• 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
• 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

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.

肺部感染是全世界30种最常见的死亡原因中的5种，下呼吸道感染平均每年导致400万人死亡，是5岁以下儿童的主要死亡原因。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，超过2亿例，425万人死亡。由于这是一种新病毒，我们对它引起的疾病（COVID-19）的各个方面了解甚少。IPP部分有超过十年的经验，解剖先天性和适应性免疫反应的肺部病原体。因此，在这个项目中，我们利用这些经验来定义对这种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，这些介质中的许多都是既定疗法和正在进行早期临床试验的药物的靶向。因此，与SARS-CoV-2感染的进展或消退相关的脂质介质的鉴定提供了新的治疗靶点。 在2021财年，我们发现肥胖是SARS-CoV-2感染的一种强共病。 此外，我们还发现肥胖宿主的严重感染与缺乏关键脂质介质的产生有关。 我们使用k18-hACE2小鼠中的饮食诱导的肥胖小鼠模型扩展了这些研究，以更彻底地询问脂质介质和肥胖在感染中的作用。 具体目标2：表征与小鼠中的亚致死和致死SARS-CoV-2感染相关的宿主中的代谢变化 代谢的特定变化对于建立有效的先天性和适应性免疫应答至关重要。使用其他感染模型，我们发现病原体可以影响宿主适当调节这些变化的能力。此外，不同的组织具有不同的动员代谢途径的能力，这也影响疾病的进展和解决。使用各种体内和体外技术，包括但不限于活体动物成像，评估靶组织和外周组织的代谢物和脂质，流式细胞术和体外代谢通量评估，我们将确定SARS-CoV-2感染如何改变宿主代谢以引起疾病。此外，我们将确定哪些途径和介质需要解决感染。通过将这些结果与我们从人体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细胞在保护小鼠免受SARS-CoV-2感染中的作用。 亚致死感染或疫苗接种后T细胞在肺中的产生和保留对于有效、持久的免疫力的发展是必不可少的。目前，还没有关于在已经解决感染或接受疫苗的宿主中存在或不存在针对SARS-CoV-2的驻留T细胞的数据。我们已经确定亚致死性感染导致肺中常驻T细胞群体的发展，但是这些细胞不足以赋予初宿主免疫力。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细胞无法自行提供保护性免疫反应。 具体目标4：长期COVID对于从SARS-CoV-2感染中恢复的人来说是一个日益严重的问题。 对这种多症状的情况了解甚少。 我们正在开发一种Long COVID模型，特别强调在小鼠模型中解决亚致死SARS-CoV-2感染后的肺和肺功能。 我们将深入了解这种病毒如何在清除感染性病毒粒子后很长时间内损害肺部环境。 我们已经开始在k18-hACE2小鼠模型中开发长期COVID模型，并正在利用我们在其他传染病和肺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。 遥测也将用于获得感染后肺功能的真实的时间测量。

项目成果

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)
• 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.

• DOI: 10.4049/immunohorizons.2300048
• 发表时间: 2023-07-01
• 期刊: ImmunoHorizons
• 作者: Jessop F;Schwarz B;Bohrnsen E;Miltko M;Shaia C;Bosio CM
• 通讯作者: Bosio CM