Lactate as a Driver of Inflammation and Virulence in SARS-Coronavirus Infections

乳酸作为 SARS 冠状病毒感染中炎症和毒力的驱动因素

基本信息

批准号：
10252304
负责人：
Ubaldo Martinez Outschoorn
金额：
$ 15.6万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-11 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252304
关键词：
Adrenal Cortex Hormones Adult Respiratory Distress Syndrome Anti-Inflammatory Agents Apoptosis Apoptosis Regulation Gene Area Automobile Driving BCL2 gene Binding Biochemical Biology Carcinoma Cell Compartmentation Cells Cessation of life Clinical Trials Coronavirus Coronavirus Infections Coupled Coupling Cyclin D1 Data Disease Down-Regulation Drug Targeting Effectiveness Fibroblasts Future Genes Genetic Epistasis Glycolysis Growth HIF1A gene Homeostasis Human IL6 gene In Vitro Infection Inflammation Inflammatory Inflammatory Response Link Lung Malignant Epithelial Cell Malignant Neoplasms Mediating Metabolic Metabolism Mitochondria Modeling Mus Outcome Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patients Pentosephosphate Pathway Pharmaceutical Preparations Public Health Risk Risk Factors Role SARS coronavirus Sampling Signal Transduction Stromal Cells T-Lymphocyte TGFB1 gene TP53 gene Testing Therapeutic Tissues Toxic effect Transforming Growth Factor beta Variant Viral Virulence base cancer cell caveolin 1 cytokine ductal breast carcinoma experimental study exposure to cigarette smoke improved outcome in vivo inhibitor/antagonist knock-down macrophage metabolic abnormality assessment mitochondrial fitness novel outcome prediction overexpression patient subsets sound tumor tumor growth tumor microenvironment uptake

项目摘要

Aggressive cancer with lung involvement and/or driven by cigarette smoke exposure is a risk factor for death in the context of severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) infection. Hence, there is great need to understand factors driving SARS-CoV-2 virulence in the context of aggressive cancer. Patients with SARS-CoV-2 infection are mainly dying from a massive inflammatory response and a severe inflammatory state is also commonly observed with aggressive cancer. Metabolism is the area of biology that studies how cells obtain and utilize energy containing molecules. Lactate is among the most common metabolites in virally infected tissues and cancer. Altered metabolism of inflammatory cells such as macrophages, fibroblasts and T cells is a hallmark of aggressive cancer and may be necessary for the severe inflammatory response to SARSCoV-2 infection. Studies from our group have shown that lactate metabolism drives inflammation in aggressive cancers. Our overall hypothesis is that increased lactate metabolism drives the severe inflammatory state of aggressive cancer, which is increased in the context of SARS-coronavirus infection. Anti-inflammatory drugs in the context of cancer or severe infections have not been effective. The lack of effectiveness might be due to an excessively narrow spectrum (e.g. inhibitors of a particular cytokine) or conversely might be due to toxicity from excessively broad targets (e.g. corticosteroids). However, inhibitors of lactate metabolism may be able to achieve homeostasis with reduced inflammation, thus improving outcomes with SARS-coronavirus infection in the context of aggressive cancer. In Aim 1, we will determine the role of lactate metabolism on SARS-coronavirus virulence in the context of aggressive cancer. In Aim 2 we will determine the role of lactate metabolism in modulating the inflammatory response in SARS-coronavirus infection in the context of aggressive cancer. Understanding the role of lactate metabolism on inflammation and the risk of dying from SARS-coronavirus infections may provide opportunities to develop new treatments for this devastating infection in patients with aggressive cancer.

在严重的急性呼吸窘迫综合征冠状病毒-2（SARS-COV-2）感染的背景下，肺部受累和/或受香烟烟雾暴露的侵略性癌症是死亡的危险因素。因此，在侵略性癌症的背景下，迫切需要了解驱动SARS-COV-2毒力的因素。 SARS-COV-2感染的患者主要死于大规模炎症反应，并且通常患有侵袭性癌症患有严重的炎症状态。代谢是研究细胞如何获得和利用含有分子的生物学领域。乳酸是病毒感染组织和癌症中最常见的代谢产物之一。炎性细胞（例如巨噬细胞，成纤维细胞和T细胞）的代谢改变是侵袭性癌症的标志，对于对SARSCOV-2感染的严重炎症反应可能是必要的。我们小组的研究表明，乳酸代谢会驱动侵袭性癌症的炎症。我们的总体假设是，增加的乳酸代谢驱动了严重的侵袭性癌症的炎症状态，在SARS-Coronavirus感染的背景下，乳酸代谢会增加。在癌症或严重感染的情况下，抗炎药尚未有效。缺乏有效性可能是由于光谱过度（例如，特定细胞因子的抑制剂）或相反可能是由于过度广泛的靶标（例如皮质类固醇）引起的。但是，乳酸代谢的抑制剂可能能够通过炎症减少来实现稳态，从而改善了侵袭性癌症中SARS-核负病毒感染的结局。在AIM 1中，我们将确定乳酸代谢在侵袭性癌症背景下对SARS-Coronaverus毒力的作用。在AIM 2中，我们将确定乳酸代谢在调节侵袭性癌症中SARS-核纳病毒感染中炎症反应中的作用。了解乳酸代谢对炎症的作用以及因SARS-核负病毒感染而死的风险，可能会为患有侵略性癌症患者的这种毁灭性感染开发新的治疗方法。