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

Judy D Day,Carson C Chow,Yoram Vodovotz,Soojin Park,Benjamin L Ranard,Harinder Singh

doi:10.3389/fimmu.2021.754127

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.

Highlights

The COVID-19 pandemic has been characterized by diverse clinical manifestations that have been associated with varying host immuno-inflammatory responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus
The overall design and execution of this study involved 1) the generation of a parsimonious mathematical model based on our core hypothesis [namely that a damage-associated molecular pattern (DAMP)-centered response to SARSCoV-2 can result in dynamically distinct biological and clinical trajectories] depending on the relative interactions among virus-infected cells, the innate immune response to DAMPs that are released from damaged or dysfunctional tissue, and the adaptive immune response triggered by innate immune activation); 2) initial calibration of viral inoculum using published data on experimental SARS-CoV-2 infection; 3) further calibration of viral inoculum to data from COVID-19 patients followed by model simulations revealing distinct disease trajectories that correspond with clinical data from exemplary patients; and 4) simulations of anti-inflammatory therapy and COVID-19 vaccination
To build our mathematical model, we posited that the virusinfected epithelial cells in the respiratory tract signal in a bifurcated manner either via pathogenassociated molecular patterns (PAMPs) or through cellular damage and/or dysfunction via DAMPs, inducing activation of virusspecific adaptive immune responses via innate cell activation (Figure 1)

Summary

Introduction

The COVID-19 pandemic has been characterized by diverse clinical manifestations that have been associated with varying host immuno-inflammatory responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. These phenotypes, which include large numbers of asymptomatic carriers [1,2,3], have ranged from moderate to severely ill patients [4, 5], those with extra-pulmonary manifestations [6], and with persistent disease [“long-haulers” [7,8,9]]. The studies have emphasized the presence of an imbalanced or overwhelming immune-inflammatory response in severe disease [16,17,18]

Methods

Results

Conclusion