TY - JOUR
T1 - Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19
T2 - Mechanistic Insights from a Whole-Body Infection Dynamics Model
AU - Dogra, Prashant
AU - Ruiz-Ramírez, Javier
AU - Sinha, Kavya
AU - Butner, Joseph D.
AU - Peláez, Maria J.
AU - Rawat, Manmeet
AU - Yellepeddi, Venkata K.
AU - Pasqualini, Renata
AU - Arap, Wadih
AU - Sostman, H. Dirk
AU - Cristini, Vittorio
AU - Wang, Zhihui
N1 - © 2020 American Chemical Society.
PY - 2021/2/12
Y1 - 2021/2/12
N2 - 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.
AB - 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.
KW - COVID-19
KW - SARS-CoV-2
KW - in silico clinical trials
KW - mathematical modeling
KW - pharmacokinetics
KW - viral dynamics
UR - http://www.scopus.com/inward/record.url?scp=85100064647&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100064647&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.0c00183
DO - 10.1021/acsptsci.0c00183
M3 - Article
C2 - 33615177
AN - SCOPUS:85100064647
SN - 2575-9108
VL - 4
SP - 248
EP - 265
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 1
ER -