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

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.