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Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model
[Image: see text] 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 (...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805603/ https://www.ncbi.nlm.nih.gov/pubmed/33615177 http://dx.doi.org/10.1021/acsptsci.0c00183 |
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author | Dogra, Prashant Ruiz-Ramírez, Javier Sinha, Kavya Butner, Joseph D. Peláez, Maria J. Rawat, Manmeet Yellepeddi, Venkata K. Pasqualini, Renata Arap, Wadih Sostman, H. Dirk Cristini, Vittorio Wang, Zhihui |
author_facet | Dogra, Prashant Ruiz-Ramírez, Javier Sinha, Kavya Butner, Joseph D. Peláez, Maria J. Rawat, Manmeet Yellepeddi, Venkata K. Pasqualini, Renata Arap, Wadih Sostman, H. Dirk Cristini, Vittorio Wang, Zhihui |
author_sort | Dogra, Prashant |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-7805603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-78056032021-01-22 Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model Dogra, Prashant Ruiz-Ramírez, Javier Sinha, Kavya Butner, Joseph D. Peláez, Maria J. Rawat, Manmeet Yellepeddi, Venkata K. Pasqualini, Renata Arap, Wadih Sostman, H. Dirk Cristini, Vittorio Wang, Zhihui ACS Pharmacol Transl Sci [Image: see text] 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. American Chemical Society 2020-12-30 /pmc/articles/PMC7805603/ /pubmed/33615177 http://dx.doi.org/10.1021/acsptsci.0c00183 Text en © 2020 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Dogra, Prashant Ruiz-Ramírez, Javier Sinha, Kavya Butner, Joseph D. Peláez, Maria J. Rawat, Manmeet Yellepeddi, Venkata K. Pasqualini, Renata Arap, Wadih Sostman, H. Dirk Cristini, Vittorio Wang, Zhihui Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model |
title | Innate Immunity Plays a Key Role in Controlling Viral
Load in COVID-19: Mechanistic Insights from a Whole-Body Infection
Dynamics Model |
title_full | Innate Immunity Plays a Key Role in Controlling Viral
Load in COVID-19: Mechanistic Insights from a Whole-Body Infection
Dynamics Model |
title_fullStr | Innate Immunity Plays a Key Role in Controlling Viral
Load in COVID-19: Mechanistic Insights from a Whole-Body Infection
Dynamics Model |
title_full_unstemmed | Innate Immunity Plays a Key Role in Controlling Viral
Load in COVID-19: Mechanistic Insights from a Whole-Body Infection
Dynamics Model |
title_short | Innate Immunity Plays a Key Role in Controlling Viral
Load in COVID-19: Mechanistic Insights from a Whole-Body Infection
Dynamics Model |
title_sort | innate immunity plays a key role in controlling viral
load in covid-19: mechanistic insights from a whole-body infection
dynamics model |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805603/ https://www.ncbi.nlm.nih.gov/pubmed/33615177 http://dx.doi.org/10.1021/acsptsci.0c00183 |
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