Role and Mitigation of Inflammasomes and Inflammation During COVID-19

Abstract The COVID-19 pandemic caused by SARS-CoV-2 has resulted in swift and catastrophic losses of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most detrimental outcomes of COVID-19 infection that can lead to the rapid deterioration and death of patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of inflammatory cytokines during the late stages of COVID-19. The master cytokines that are thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor (TNF). Currently several clinical trials have already been initiated to test the efficacy of biologic inhibitors to target these pathways. However, in many cases, the mechanism and impact of these cytokines during ARDS are poorly understood. An indepth mechanistic understanding of cytokine induction is important because this understanding will significantly impact the design and success of ARDS treatment. This application focuses on the role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine, IL-1β, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase 1 activation, which then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. In addition to the release of IL-1β and IL-18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is comprised of a receptor or sensor, with the most prominent ones represented by NLRP1, NLRP3, NLRP6, NLRC4 and AIM2. It also includes an adaptor molecule ASC (apoptosis- associated speck-like protein containing a CARD), and the effector caspase-1. Each receptor or sensor can be activated by specific pathogen products called PAMPs or cell damage associated molecules called DAMPs. NLRP3 is the most studied member since it is activated by a large list of stimulators. Studies of other coronavirus such as SARS show inflammasome activation by key viral proteins. Expression data from COVID-19 patients also show dramatic increases of inflammasome sensors in the bronchial alveolar lavage of COVID-19 patients. However the mechanism of inflammasome activation by SARS-CoV-2, especially in the human system, remains unknown. This proposal will identify the viral protein that activates human inflammasome, and further define the specific human inflammasome sensor/receptor that mediates the response. We will then design ways to reduce inflammasome activation during SARS-CoV-2 infection using established therapeutics as well as new approaches to broadly attenuate inflammatory cytokines.