COVID-19: Lung-Centric Immunothrombosis

Abstract

The respiratory tract is the major site of infection by SARS-CoV-2, the virus causing COVID-19. The pulmonary infection can lead to acute respiratory distress syndrome (ARDS) and ultimately, death. An excessive innate immune response plays a major role in the development of ARDS in COVID-19 patients. In this scenario, activation of lung epithelia and resident macrophages by the virus results in local cytokine production and recruitment of neutrophils. Activated neutrophils extrude a web of DNA-based cytoplasmic material containing antimicrobials referred to as neutrophil extracellular traps (NETs). While NETs are a defensive strategy against invading microbes, they can also serve as a nidus for accumulation of activated platelets and coagulation factors, forming thrombi. This immunothrombosis can result in occlusion of blood vessels leading to ischemic damage. Herein we address evidence in favor of a lung-centric immunothrombosis and suggest a lung-centric therapeutic approach to the ARDS of COVID-19.

Keywords: COVID-19; NET; SARS-CoV-2; acute respiratory distress syndrome (ARDS); coronavirus; cytokine storm.

Figure 1

Schematic of lung-centric inflammation and immunothrombosis in response to SARS-CoV-2 infection. Resident alveolar macrophages mount an inflammatory response to infection of the lungs by SARS-CoV-2. Macrophages detect viral material e.g., pathogen-associated molecular patterns (PAMPs). PAMPs activate the NFκB pathway which generates pro-IL-1β and components of the inflammasome. Assembly and functional activation of the inflammasome results in caspase-mediated cleavage of pro-IL-1β to the mature IL-1β. Caspase cleavage of gasdermin D (GSDMD) allows it to enter the plasma membrane and oligomerize, forming pores. IL-1β as well as other inflammatory mediators, such as damage-associated molecular patterns (DAMPs) exit the macrophage through the GSDMD pores. The inflammatory response is amplified by feed-forward mechanisms and recruitment of additional leukocytes, e.g., neutrophils. Activated neutrophils can extrude neutrophil extracellular traps (NETs), a meshwork of decondensed DNA decorated with granule-derived proteases and antimicrobials. Inflammasome-derived caspase as well as granule-derived elastase activate GSDMD to form the pores for NET release. NETs formed in the alveolar space can induce lung injury while NETs generated within blood vessels sequester platelets and coagulation factors to promote thrombogenesis. Modified from (Tall and Westerterp, 2019).