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

• 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
• 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

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.

在严重急性呼吸窘迫综合征冠状病毒-2 (SARS-CoV-2) 感染的情况下，累及肺部和/或由香烟烟雾引起的侵袭性癌症是死亡的危险因素。因此，非常需要了解在侵袭性癌症背景下驱动 SARS-CoV-2 毒力的因素。 SARS-CoV-2 感染患者主要死于大规模炎症反应，严重的炎症状态也常见于侵袭性癌症。新陈代谢是研究细胞如何获取和利用含能分子的生物学领域。乳酸是病毒感染组织和癌症中最常见的代谢物之一。巨噬细胞、成纤维细胞和 T 细胞等炎症细胞代谢的改变是侵袭性癌症的标志，可能是 SARSCoV-2 感染引起的严重炎症反应所必需的。我们小组的研究表明，乳酸代谢会导致侵袭性癌症的炎症。我们的总体假设是，乳酸代谢的增加会导致侵袭性癌症的严重炎症状态，这种状态在 SARS 冠状病毒感染的情况下会加剧。抗炎药物在癌症或严重感染的情况下效果不佳。缺乏有效性可能是由于谱过于窄（例如特定细胞因子的抑制剂），或者相反可能是由于过于广泛的靶标（例如皮质类固醇）的毒性。然而，乳酸代谢抑制剂可能能够通过减少炎症来实现体内平衡，从而改善侵袭性癌症背景下 SARS 冠状病毒感染的结果。在目标 1 中，我们将确定乳酸代谢在侵袭性癌症背景下对 SARS 冠状病毒毒力的作用。在目标 2 中，我们将确定乳酸代谢在调节侵袭性癌症背景下 SARS 冠状病毒感染炎症反应中的作用。了解乳酸代谢对炎症的作用以及死于 SARS 冠状病毒感染的风险可能为开发针对侵袭性癌症患者这种毁灭性感染的新疗法提供机会。