Modeling elucidates the immune underpinnings of the heterogeneous outcomes of SARS-CoV-2 infection

Budhaditya Chatterjee

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 diverse outcomes remains unclear. We developed a mathematical model of within-host SARS-CoV-2 dynamics and applied it to longitudinal viral load data from multiple published datasets to elucidate the immune underpinnings of the heterogeneous outcomes. Our model incorporated the essential features of the innate immune and CD8 T-cell responses. We fit the model to the data using a non-linear mixed effects approach. Our model provided excellent fits to the data and offered insights into the roles of the two immune arms in determining the severity of infection. 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. 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 additional confounding clinical observations, including the occurrence of multiple peaks in viral load, viral recrudescence after symptom loss, and prolonged viral positivity. These insights have implications for interventions aimed at preventing severe disease and for understanding the differences between viral variants.

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