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.

肺部感染是世界上30种最常见的死亡原因中的5种，下呼吸道感染每年平均导致400万人死亡，是5岁以下儿童的主要死亡原因。目前，我们正处于由肺部病原体SARS-CoV-2引起的大流行之中。到目前为止，感染和死亡人数已超过其他更典型的呼吸道感染，超过2亿例和425万人死亡。由于这是一种新病毒，我们对它引起的疾病(新冠肺炎)的方方面面了解很少。IPP部门有十多年的经验，剖析对肺部病原体的先天和获得性免疫反应。因此，在这个项目中，我们利用这一经验来定义对这种病毒的先天和获得性免疫反应的独特特征，特别强调亚致命和致命疾病期间发生的代谢和脂类扰动。 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。 脂质和脂质介体是启动和维持炎症反应以及消解感染后炎症反应的重要分子。幸运的是，这些介体中的许多要么是现有疗法的靶向，要么是正在进行早期临床试验的药物。因此，识别与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。 在2021财年，我们发现肥胖是SARS-CoV-2感染的强烈共病。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小鼠的饮食诱导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。 特定目标2：描述与小鼠的亚致死性和致死性SARS-CoV-2感染相关的宿主的代谢变化 新陈代谢的特定变化对于建立有效的先天和获得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适当调节这些转变的能力。此外，不同的组织动员代谢途径的能力也不同，这也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、靶组织和外周组织的代谢物和脂质的评估、流式细胞术和体外代谢流量的评估，我们将确定SARS-CoV-2感染如何改变宿主代谢而导致疾病。此外，我们将确定需要哪些途径和介体来解决感染问题。通过将这些结果与我们从人类样本中获得的结果重叠，我们将为SARS-CoV-2的治疗干预确定新的靶点。 具体目标3：确定常驻T细胞和循环T细胞在小鼠抵抗SARS-CoV-2感染中的作用。 在亚致死感染或疫苗接种后，T细胞在肺内的产生和保留对于发展有效、持久的免疫是必不可少的。目前，在已经解决感染或接种疫苗的宿主中，没有关于针对SARS-CoV-2的常驻T细胞的存在或缺失的数据。我们已经确定，亚致死性感染导致肺内常驻T细胞群的发展，但这些细胞不足以在初治宿主中授予免疫力。我们还将分析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细胞本身不能提供保护性免疫反应。 具体目标4：长期冠状病毒感染对SARS-CoV-2感染康复者来说是一个日益严重的问题。对于这种多症状症状，人们知之甚少。我们正在开发一种长期冠状病毒感染的模型，特别强调在小鼠模型中解决亚致死性SARS-CoV-2感染后的肺和肺功能。我们将深入了解这种病毒是如何在清除了传染性病毒粒子后很长时间内危害肺环境的。 我们已经开始在K18-hACE2小鼠模型中开发长冠状病毒感染模型，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感染SARS-CoV-2对肺功能的影响。还将利用遥测技术实时测量感染后的肺功能。

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