The primary distinction between severe and mild COVID-19 infections is the immune response. Disease severity and fatality has been observed to correlate with lymphopenia, cytokine storm, dysregulated macrophage responses, and T cell exhaustion. However, the mechanisms driving immunopathology in COVID-19 remain unclear. To pinpoint possible causes of dysregulated immune dynamics in severe cases, we have developed a within-host model of the immune response to SARS-CoV-2 infection. Our model links viral kinetics to the innate and adaptive immune response by accounting for the interactions between viral load, viral strain, infected and damaged lung epithelial cells, immune cell subsets (primarily tissue-resident and inflammatory macrophages, CD8+ T cells, monocytes, and neutrophils), and inflammatory cytokines (i.e., IFN-1, GM-CSF, G-CSF, IL-6). Our model successfully recapitulates mild and severe COVID-19 presentations. Through the expansion of a realistic virtual patient cohort, we analyzed the mechanisms regulating the diversity of immune responses to SARS-CoV-2 to identify those that predispose individuals to particularly severe disease. Our results suggest that virtual patients with impaired IFN-1 and monocyte-to-macrophage differentiation are more likely to develop severe COVID-19, and that it is largely the immune response, not viral loads or variants, driving COVID-19 severity. Our model represents a comprehensive framework that helps to improve our understanding of SARS-CoV-2 infection dynamics and the ensuing immune response.

Dr. Morgan Craig is a Researcher at the Research Centre of the Sainte-Justine University Hospital Centre and an Assistant Professor in the Department of Mathematics and Statistics at the University of Montréal. She received her Ph.D. in Pharmaceutical Sciences from the University of Montréal and was recruited from the Department of Organismic and Evolutionary Biology at Harvard University where she did her postdoctoral training. The Quantitative and Translational Medicine Laboratory that she runs focuses on the application and implementation of quantitative approaches, particularly computational biology, to study biologically-relevant questions of large medical importance. Her work focuses on understanding how heterogeneity in patient-specific characteristics impacts on disease and treatment outcomes, with a particular emphasis on leveraging variability for treatment optimization and precision medicine. Dr. Craig’s current projects include understanding pre-leukemic hematopoietic stem cell dynamics and clonal reduction strategies, HIV treatment design and HIV cure strategies, understanding immunological networks during rare diseases and the immune response to SARS-CoV-2, and quantifying the impact of heterogeneity in a variety of solid tumours on resistance pathways and ultimate therapy success. Dr. Craig’s research is highly multidisciplinary and is conducted in close collaboration with experimentalists and clinicians.

Related publications: COVID-19 virtual patient cohort reveals immune mechanisms driving disease outcomes https://www.biorxiv.org/content/10.1101/2021.01.05.425420v1 Rapid community-driven development of a SARS-CoV-2 tissue simulator https://www.biorxiv.org/content/10.1101/2020.04.02.019075v3

For more information please got to morgancraiglab.com and follow on Twitter @lab_craig