Predicting the Kinetic Coordination of Immune Response Dynamics in SARS-CoV-2 Infection: Implications for Disease Pathogenesis

Abstract

A calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed. The model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Recently published data sets from human challenge studies with SARS-CoV-2 were used for parameter evaluation. The calibration of the mathematical model of SARS-CoV-2 infection is based on combining the parameter guesses from our earlier study of influenza A virus infection, some recent quantitative models of SARS-CoV-2 infection and clinical data-based parameter estimation of a subset of the model parameters. Hence, the calibrated mathematical model represents a theoretical exploration type of study, i.e., ‘in silico patient’ with mild-to-moderate severity phenotype, rather than a completely validated quantitative model of COVID-19 with respect to all its state-space variables. Understanding the regulation of multiple intertwined reaction components of the immune system is necessary for linking the kinetics of immune responses with the clinical phenotypes of COVID-19. Consideration of multiple immune reaction components in a single calibrated mathematical model allowed us to address some fundamental issues related to the pathogenesis of COVID-19, i.e., the sensitivity of the peak viral load to the parameters characterizing the antiviral specific response components, the kinetic coordination of the individual innate and adaptive immune responses, and the factors favoring a prolonged viral persistence. The model provides a tool for predicting the infectivity of patients, i.e., the amount of virus which is transmitted via droplets from the person infected with SARS-CoV-2, depending on the time of infection. The thresholds for variations of the innate and adaptive response parameters which lead to a prolonged persistence of SARS-CoV-2 due to the loss of a kinetic response synchrony/coordination between them were identified.

Mathematical and Computational Biology of Viruses at the Molecular or Cellular Levels

“…The improved kinetic model for HDV-HBV interaction [16] ameliorates the deficiencies of past models [17,18], and the initial attempt in [13] presented a new concept, but it only considered scarce data from very few patients. Next, in the paper by Grebennikov et al [19], a calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed, and the new model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Thus far, more than a dozen of mathematical models of SARS-CoV-2 infection have been developed, such as in [20], and the study in [19] is unique in that it highlights the value of mathematical modelling in gaining a mechanistic view of the kinetic regulations of SARS-CoV-2 infections and antiviral immune responses.…”

“…Next, in the paper by Grebennikov et al [19], a calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed, and the new model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Thus far, more than a dozen of mathematical models of SARS-CoV-2 infection have been developed, such as in [20], and the study in [19] is unique in that it highlights the value of mathematical modelling in gaining a mechanistic view of the kinetic regulations of SARS-CoV-2 infections and antiviral immune responses. Finally, it is worthwhile to mention that viral kinetic models can become more complicated in a variety of ways, an example being HCV multiscale models [21][22][23][24], presenting new mathematical challenges that could be the topic of a future Special Issue.…”

Exploring the therapeutic potential of defective interfering particles in reducing the replication of SARS-CoV-2

“…From a mathematical modelling perspective, a long-standing effort exists to describe transmission dynamics at the population and within-host levels (see Ref. [18] and Refs. [19,20].…”

“…From a mathematical modelling perspective, a long-standing effort exists to describe transmission dynamics at the population and within-host levels (see Ref. [18] and references therein). At the within-host level DIPs, as therapeutics, have been studied in Refs.…”

Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses

“…These models were also the first to suggest that viral rebound may occur in the context of early antiviral treatments 11 . However, early modeling studies only considered data from a small number of infected individuals 11,20,[22][23][24][25][26][27][31][32][33][34][35] , and often drew either entirely from previously uninfected and/or unvaccinated cohorts 13 . Another consistent limitation was that most available data did not capture early timepoints during the pre-symptomatic phase of infection.…”