Modeling recapitulates the heterogeneous outcomes of SARS-CoV-2 infection and quantifies the differences in the innate immune and CD8 T-cell responses between patients experiencing mild and severe symptoms

Abstract

SARS-CoV-2 infection results in highly heterogeneous outcomes, from cure without symptoms to acute respiratory distress and death. Empirical evidence points to the prominent roles of innate immune and CD8 T-cell responses in determining the outcomes. However, how these immune arms act in concert to elicit the outcomes remains unclear. Here, we developed a mathematical model of within-host SARS-CoV-2 infection that incorporates the essential features of the innate immune and CD8 T-cell responses. Remarkably, by varying the strengths and timings of the two immune arms, the model recapitulated the entire spectrum of outcomes realized. Furthermore, model predictions offered plausible explanations of several confounding clinical observations, including the occurrence of multiple peaks in viral load, viral recrudescence after symptom loss, and prolonged viral positivity. We applied the model to analyze published datasets of longitudinal viral load measurements from patients exhibiting diverse outcomes. The model provided excellent fits to the data. The best-fit parameter estimates indicated a nearly 80-fold stronger innate immune response and an over 200-fold more sensitive CD8 T-cell response in patients with mild compared to severe infection. These estimates provide quantitative insights into the likely origins of the dramatic inter-patient variability in the outcomes of SARS-CoV-2 infection. The insights have implications for interventions aimed at preventing severe disease and for understanding the differences between viral variants. Understanding the origins of the highly diverse outcomes of SARS-CoV-2 infection, ranging from clearance without symptoms to death, is an important challenge. Growing evidence points to the crucial roles of innate immune and CD8 T-cell responses in determining the outcomes. Delineating and quantifying the roles of these two immune arms would help better understand the origins of the diverse outcomes and inform intervention strategies aimed at preventing severe disease. Here, we developed a mathematical model of within-host SARS-CoV-2 dynamics and applied it to analyze clinical datasets comprising longitudinal viral load measurements from patients experiencing different severities of infection. Model predictions showed how a dynamical interplay between the strengths and the timings of innate and CD8 T-cell responses could recapitulate the diverse outcomes observed. Furthermore, the model provided excellent fits to the data and estimated that the innate immune and CD8 T-cell responses were nearly 80-fold and 200-fold stronger, respectively, in mildly versus severely infected patients. These estimates offer quantitative insights into the likely origins of the diverse outcomes of SARS-CoV-2 infection. We highlight potential implications for interventions and for understanding the differences between viral variants.