Immunothrombosis in Severe COVID-19 and Bacterial Sepsis, and Barriers to Biosampling-Based Translational Research

Abstract

Infection, immunity, and blood coagulation are interconnected through a process known as immunothrombosis. In cases of serious illness, such as severe COVID-19 or bacterial sepsis (life-threatening organ dysfunction caused by dysregulated host response to infection), immunothrombosis can worsen disease severity and negatively impact patient outcomes. COVID-19 exposed millions to a life-threatening illness that is linked to immunothrombosis. Despite shared features, the similarities and differences between COVID-19 and sepsis are poorly understood. In this thesis, we demonstrate pathophysiological differences in immunothrombosis between critically-ill COVID-19 patients and non-COVID septic patients with pneumonia. We also demonstrate that immunothrombosis severity was reduced in patients recruited later in the pandemic. Neutrophil extracellular traps (NETs) are prominent drivers of immunothrombosis that are elevated in sepsis. NETs are structures composed of chromatin and antimicrobial molecules released by neutrophils in response to infection. While studies have identified NETs as targets for improving septic patient outcomes, results have been conflicting and have reported that NETs limit the spread of infection while also worsening survival. We demonstrate that PAD4-deficient mice show worsened survival in a fecal-induced peritonitis model of abdominal sepsis, suggesting that NETs have a protective effect. Septic PAD4-/- mice had higher bacterial loads, lower IL-6 levels, elevated lung myeloperoxidase levels, and exacerbated lung/liver injury compared with septic wild-type mice. The investigations conducted in this thesis involved a study design that emphasized the translation of studies in the laboratory to their practical application in the clinic. Translational research is growing in Canada, but a lack of infrastructure may hinder the ability of clinical research units to effectively conduct studies. We conducted a survey to identify barriers to biosampling-based translational research in the critical care setting in Canada. These studies contribute to understanding the relationship between immunothrombosis and disease, and highlight the role of translational research in investigating them.