Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. It is important to better understand SARS-CoV-2 pathogenesis and population susceptibility to infection in order to develop effective disease management strategies. To this end, physiologically relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency of the virus for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune response, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body. Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, to understand the effects of physiological factors and underlying conditions on viral load dynamics, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load from the body. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model highlights the importance of innate immunity (interferons and resident macrophages) in controlling viral load, and the significance of timing when initiating therapy following infection.

Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective

“…Although their modeling still requires validation, in their concept they concluded about the dominant role of innate immunity due to IFNs and macrophages as well as the importance of timing when initiating therapy. 84 Overall, the conclusions from all these QSP and pharmacodynamic studies are consistent with our thinking as we have discussed in the manuscript.…”

SARS-CoV-2 Viral Shedding and Transmission Dynamics: Implications of WHO COVID-19 Discharge Guidelines

“…Variation in the time of activation of the adaptive immune response in different individuals implies that the SARS-CoV-2 virus can continue replicating and remains viable (31). In a recent study, it was found that interferons play a key role in suppressing the virus in the upper airway, while macrophages are primarily responsible for viral clearance in the lungs, mononuclear phagocyte system (MPS), and other systemic sites (32). Therefore, the rate at which lung and MPS macrophages clear the virus influences the viral load in both the lungs and the plasma (32).…”

“…In a recent study, it was found that interferons play a key role in suppressing the virus in the upper airway, while macrophages are primarily responsible for viral clearance in the lungs, mononuclear phagocyte system (MPS), and other systemic sites (32). Therefore, the rate at which lung and MPS macrophages clear the virus influences the viral load in both the lungs and the plasma (32). In patients with defective immune systems, viral clearance will depend on the excretion of the virus through the bile duct, which can take weeks.…”

Do Pandemics Obey the Elliott Wave Principle of Financial Markets?

“…While India continues to be on the corrective wave 2, Brazil is exhibiting an impulsive wave 3 that can be attributed to the revival of tourist attractions, beaches, shopping malls, and restaurants since October 2020 7 . It is important to note that in case of India, there is growing evidence that the Indian population possesses better innate immunity to SARS-CoV-2 8-10 , which indicates that any possible divergence from the sentiment-mediated wave principle may be a result of the additional biological variable at play in this population.…”