Divergent COVID-19 Disease Trajectories Predicted by a DAMP-Centered Immune Network Model

Front Immunol. 2021 Oct 28:12:754127. doi: 10.3389/fimmu.2021.754127. eCollection 2021.

Abstract

COVID-19 presentations range from mild to moderate through severe disease but also manifest with persistent illness or viral recrudescence. We hypothesized that the spectrum of COVID-19 disease manifestations was a consequence of SARS-CoV-2-mediated delay in the pathogen-associated molecular pattern (PAMP) response, including dampened type I interferon signaling, thereby shifting the balance of the immune response to be dominated by damage-associated molecular pattern (DAMP) signaling. To test the hypothesis, we constructed a parsimonious mechanistic mathematical model. After calibration of the model for initial viral load and then by varying a few key parameters, we show that the core model generates four distinct viral load, immune response and associated disease trajectories termed "patient archetypes", whose temporal dynamics are reflected in clinical data from hospitalized COVID-19 patients. The model also accounts for responses to corticosteroid therapy and predicts that vaccine-induced neutralizing antibodies and cellular memory will be protective, including from severe COVID-19 disease. This generalizable modeling framework could be used to analyze protective and pathogenic immune responses to diverse viral infections.

Keywords: COVID-19; DAMP; SARS-CoV2; danger signal; immune response; inflammation; mathematical model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Adult
  • Aged
  • Alarmins / immunology*
  • Anti-Inflammatory Agents / therapeutic use
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • COVID-19 Drug Treatment*
  • COVID-19 Vaccines
  • COVID-19* / diagnosis
  • COVID-19* / immunology
  • COVID-19* / virology
  • Humans
  • Middle Aged
  • Models, Biological*
  • Reproducibility of Results
  • SARS-CoV-2*
  • Viral Load

Substances

  • Adrenal Cortex Hormones
  • Alarmins
  • Anti-Inflammatory Agents
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines