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

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一个危险因素。因此，有必要了解在侵袭性癌症背景下驱动SARS-CoV-2毒力的因素。感染SARS-CoV-2的患者主要死于大量炎症反应，侵袭性癌症也常出现严重的炎症状态。代谢是研究细胞如何获取和利用含有分子的能量的生物学领域。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感染引起严重炎症反应的必要条件。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，乳酸代谢的增加推动了侵袭性癌症的严重炎症状态，这在sars冠状病毒感染的背景下会增加。抗炎药在癌症或严重感染的情况下没有效果。缺乏有效性可能是由于范围过窄（例如，特定细胞因子的抑制剂）或相反，可能是由于毒性靶标过广（例如，皮质类固醇）。然而，乳酸代谢抑制剂可能能够在减少炎症的情况下实现体内平衡，从而改善侵袭性癌症背景下sars冠状病毒感染的预后。在Aim 1中，我们将确定在侵袭性癌症背景下乳酸代谢对sars冠状病毒毒力的作用。在Aim 2中，我们将确定在侵袭性癌症背景下，乳酸代谢在调节sars冠状病毒感染炎症反应中的作用。了解乳酸代谢对炎症和死于sars冠状病毒感染的风险的作用，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。

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.