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. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, 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 for infection) of the virus and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following parameter quantification 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, we ranked model parameters through sensitivity analysis for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination were simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy after infection.

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.…”

The timing of natural killer cell response in coronavirus infection: a concise model perspective

“…Predicted by these models, the virus population peak around symptom onset and its subsequent decay are the main elements of heterogeneous disease kinetics. A larger and detailed full-scale model [61] simulates the viral infection dynamics at the whole-body level while highlighting the crucial roles of innate immunity. In this light, the contribution of our model is its simplicity and focusing on the early blockade to the virus replication by the innate immunity.…”

Advancing therapies for viral infections using mechanistic computational models of the dynamic interplay between the virus and host immune response

“…Interferons (IFNs) are the frontline defenders of the innate immune system, both interfering with infection of host cells and reducing viral replication inside infected cells. Recent models have explored the importance of innate immune response feedback pathways in determining the outcome of disease in individuals [ 22 • , 23 ]. The target-cell-limited modeling framework has been extended to analyze the effect of interferon-α therapy in treatment of Hepatitis C virus (HCV) infection [ 24 ] and to evaluate the relative importance of the two modes of IFN action (reducing production of virions by infected cells and reducing de novo rates of cell infection) [ 24 ].…”