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
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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.
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SciScore for 10.1101/2021.06.15.21258935: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources MATLAB (version R2020a) was used to estimate the fixed points of the system and to determine the nature of their stability. MATLABsuggested: (MATLAB, RRID:SCR_001622)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has limitations. First, we neglected the role that cytokines play in the expansion of CD8 T-cells (92) because fits of our model incorporating such …
SciScore for 10.1101/2021.06.15.21258935: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources MATLAB (version R2020a) was used to estimate the fixed points of the system and to determine the nature of their stability. MATLABsuggested: (MATLAB, RRID:SCR_001622)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has limitations. First, we neglected the role that cytokines play in the expansion of CD8 T-cells (92) because fits of our model incorporating such an effect to the available data were poor (supplementary text section B). Perhaps, a larger patient cohort may improve the fits and allow incorporating the latter effect. Second, our model did not incorporate any negative effect of immunopathology on the immune response; for instance, lymphopenia (15, 93), which is generally thought to be caused by immunopathology, could compromise the immune response. Third, we employed a simplified model of CD8 T-cell exhaustion, following earlier studies (30–32), which allows exhaustion to be reversed fully upon lowering antigen levels. Recent studies have demonstrated that exhaustion is reversible only in a subset of exhausted cells (83). Notwithstanding, we expect our key inferences on the roles of the innate and the CD8 T-cell responses in determining the heterogeneous outcomes of SARS-CoV-2 infection to hold.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04333914 Recruiting Prospective Study in Patients With Advanced or Metastatic Ca… NCT04413838 Not yet recruiting Efficiency and Security of NIVOLUMAB Therapy in Obese Indivi… NCT04343144 Not yet recruiting Trial Evaluating Efficacy and Safety of Nivolumab (Optivo®) … NCT04356508 Not yet recruiting COVID-19: A Pilot Study of Adaptive Immunity and Anti-PD1 NCT04268537 Not yet recruiting Immunoregulatory Therapy for 2019-nCoV Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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