COVID-19 virtual patient cohort suggests immune mechanisms driving disease outcomes

Author summary Understanding of the diversity of immune responses to SARS-CoV-2 infections is critical for improving diagnostic and treatment approaches. Identifying which immune mechanisms lead to divergent outcomes can be clinically difficult, and experimental models and longitudinal data are only beginning to emerge. In response, we developed a mechanistic, mathematical and computational model of the immunopathology of COVID-19 calibrated to and independently validated against a broad set of experimental and clinical immunological data. To study the drivers of severe COVID-19, we used our model to expand a cohort of virtual patients, each with realistic disease dynamics. Our results suggest key processes that regulate the immune response to SARS-CoV-2 infection in virtual patients and suggest viable therapeutic targets, underlining the importance of a rational, multifaceted approach to studying novel pathogens using intra-host models. To understand the diversity of immune responses to SARS-CoV-2 and distinguish features that predispose individuals to severe COVID-19, we developed a mechanistic, within-host mathematical model and virtual patient cohort. Our results suggest that virtual patients with low production rates of infected cell derived IFN subsequently experienced highly inflammatory disease phenotypes, compared to those with early and robust IFN responses. In these in silico patients, the maximum concentration of IL-6 was also a major predictor of CD8(+) T cell depletion. Our analyses predicted that individuals with severe COVID-19 also have accelerated monocyte-to-macrophage differentiation mediated by increased IL-6 and reduced type I IFN signalling. Together, these findings suggest biomarkers driving the development of severe COVID-19 and support early interventions aimed at reducing inflammation.

Automated summary

The study developed a mechanistic, mathematical, and computational model to investigate the diversity of immune responses to SARS-CoV-2 and suggested potential therapeutic targets. The findings highlight the importance of using intra-host models to study novel pathogens.