Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

Moses, Melanie E.; Hofmeyr, Steven; Cannon, Judy L.; Andrews, Akil; Gridley, Rebekah; Hinga, Monica; Leyba, Kirtus; Pribisova, Abigail; Surjadidjaja, Vanessa; Tasnim, Humayra; Forrest, Stephanie; Smith, ed., Amber M.

doi:10.1371/journal.pcbi.1009735

Title: Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

Journal Article · 22 December 2021 · PLoS Computational Biology (Online)

DOI: https://doi.org/10.1371/journal.pcbi.1009735 · OSTI ID:1838923

; Hofmeyr, Steven;

;

; Gridley, Rebekah; Hinga, Monica;

;

; Surjadidjaja, Vanessa;

;

; Smith, ed., Amber M.

A key question in SARS-CoV-2 infection is why viral loads and patient outcomes vary dramatically across individuals. Because spatial-temporal dynamics of viral spread and immune response are challenging to study in vivo, we developed Spatial Immune Model of Coronavirus (SIMCoV), a scalable computational model that simulates hundreds of millions of lung cells, including respiratory epithelial cells and T cells. SIMCoV replicates viral growth dynamics observed in patients and shows how spatially dispersed infections can lead to increased viral loads. The model also shows how the timing and strength of the T cell response can affect viral persistence, oscillations, and control. By incorporating spatial interactions, SIMCoV provides a parsimonious explanation for the dramatically different viral load trajectories among patients by varying only the number of initial sites of infection and the magnitude and timing of the T cell immune response. When the branching airway structure of the lung is explicitly represented, we find that virus spreads faster than in a 2D layer of epithelial cells, but much more slowly than in an undifferentiated 3D grid or in a well-mixed differential equation model. These results illustrate how realistic, spatially explicit computational models can improve understanding of within-host dynamics of SARS-CoV-2 infection.

View Journal Article

Cite

Export

Save

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1838923

Journal Information:: PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 12 Vol. 17; ISSN 1553-7358

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

References (51)

Mathematical modeling of interaction between innate and adaptive immune responses in COVID‐19 and implications for viral pathogenesis Du, Sean Quan; Yuan, Weiming Journal of Medical Virology, Vol. 92, Issue 9 https://doi.org/10.1002/jmv.25866	journal	May 2020
Abnormal lung quantification in chest CT images of COVID‐19 patients with deep learning and its application to severity prediction Shan, Fei; Gao, Yaozong; Wang, Jun Medical Physics, Vol. 48, Issue 4 https://doi.org/10.1002/mp.14609	journal	March 2021
Modeling Intercellular Interactions in Early Mycobacterium Infection Warrender, Christina; Forrest, Stephanie; Koster, Frederick Bulletin of Mathematical Biology, Vol. 68, Issue 8 https://doi.org/10.1007/s11538-006-9103-y	journal	May 2006
Masks Do More Than Protect Others During COVID-19: Reducing the Inoculum of SARS-CoV-2 to Protect the Wearer Gandhi, Monica; Beyrer, Chris; Goosby, Eric Journal of General Internal Medicine, Vol. 35, Issue 10 https://doi.org/10.1007/s11606-020-06067-8	journal	July 2020
Models of human lung airways and their application to inhaled particle deposition Yeh, H.; Schum, G. Bulletin of Mathematical Biology, Vol. 42, Issue 3 https://doi.org/10.1016/S0092-8240(80)80060-7	journal	January 1980
Clinically Applicable AI System for Accurate Diagnosis, Quantitative Measurements, and Prognosis of COVID-19 Pneumonia Using Computed Tomography Zhang, Kang; Liu, Xiaohong; Shen, Jun Cell, Vol. 181, Issue 6 https://doi.org/10.1016/j.cell.2020.04.045	journal	June 2020
Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals Grifoni, Alba; Weiskopf, Daniela; Ramirez, Sydney I. Cell, Vol. 181, Issue 7 https://doi.org/10.1016/j.cell.2020.05.015	journal	June 2020
Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity Rydyznski Moderbacher, Carolyn; Ramirez, Sydney I.; Dan, Jennifer M. Cell, Vol. 183, Issue 4 https://doi.org/10.1016/j.cell.2020.09.038	journal	November 2020
Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients Tan, Anthony T.; Linster, Martin; Tan, Chee Wah Cell Reports, Vol. 34, Issue 6 https://doi.org/10.1016/j.celrep.2021.108728	journal	February 2021
Estimation of the incubation period of COVID-19 using viral load data Ejima, Keisuke; Kim, Kwang Su; Ludema, Christina Epidemics, Vol. 35 https://doi.org/10.1016/j.epidem.2021.100454	journal	June 2021
Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis Yang, Jing; Zheng, Ya; Gou, Xi International Journal of Infectious Diseases, Vol. 94 https://doi.org/10.1016/j.ijid.2020.03.017	journal	May 2020
Inoculum at the time of SARS-CoV-2 exposure and risk of disease severity Guallar, María Pilar; Meiriño, Rosa; Donat-Vargas, Carolina International Journal of Infectious Diseases, Vol. 97 https://doi.org/10.1016/j.ijid.2020.06.035	journal	August 2020
CXCR3 Chemokine Receptor Enables Local CD8+ T Cell Migration for the Destruction of Virus-Infected Cells Hickman, Heather D.; Reynoso, Glennys V.; Ngudiankama, Barbara F. Immunity, Vol. 42, Issue 3 https://doi.org/10.1016/j.immuni.2015.02.009	journal	March 2015
In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity Halle, Stephan; Keyser, Kirsten Anja; Stahl, Felix Rolf Immunity, Vol. 44, Issue 2 https://doi.org/10.1016/j.immuni.2016.01.010	journal	February 2016
Agent-based modeling of host–pathogen systems: The successes and challenges Bauer, Amy L.; Beauchemin, Catherine A. A.; Perelson, Alan S. Information Sciences, Vol. 179, Issue 10 https://doi.org/10.1016/j.ins.2008.11.012	journal	April 2009
A spatial model of the efficiency of T cell search in the influenza-infected lung Levin, Drew; Forrest, Stephanie; Banerjee, Soumya Journal of Theoretical Biology, Vol. 398 https://doi.org/10.1016/j.jtbi.2016.02.022	journal	June 2016
Modeling the viral dynamics of SARS-CoV-2 infection Wang, Sunpeng; Pan, Yang; Wang, Quanyi Mathematical Biosciences, Vol. 328 https://doi.org/10.1016/j.mbs.2020.108438	journal	October 2020
Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells Harris, Tajie H.; Banigan, Edward J.; Christian, David A. Nature, Vol. 486, Issue 7404 https://doi.org/10.1038/nature11098	journal	May 2012
Stabilized imaging of immune surveillance in the mouse lung Looney, Mark R.; Thornton, Emily E.; Sen, Debasish Nature Methods, Vol. 8, Issue 1 https://doi.org/10.1038/nmeth.1543	journal	December 2010
ROCK regulates the intermittent mode of interstitial T cell migration in inflamed lungs Mrass, Paulus; Oruganti, Sreenivasa Rao; Fricke, G. Matthew Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-01032-2	journal	October 2017
SARS-CoV-2 viral load is associated with increased disease severity and mortality Fajnzylber, Jesse; Regan, James; Coxen, Kendyll Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-19057-5	journal	October 2020
Viral and host factors related to the clinical outcome of COVID-19 Zhang, Xiaonan; Tan, Yun; Ling, Yun Nature, Vol. 583, Issue 7816 https://doi.org/10.1038/s41586-020-2355-0	journal	May 2020
Longitudinal analyses reveal immunological misfiring in severe COVID-19 Lucas, Carolina; Wong, Patrick; Klein, Jon Nature, Vol. 584, Issue 7821 https://doi.org/10.1038/s41586-020-2588-y	journal	July 2020
A stochastic agent-based model of the SARS-CoV-2 epidemic in France Hoertel, Nicolas; Blachier, Martin; Blanco, Carlos Nature Medicine, Vol. 26, Issue 9 https://doi.org/10.1038/s41591-020-1001-6	journal	July 2020
Generalized chest CT and lab curves throughout the course of COVID-19 Kassin, Michael T.; Varble, Nicole; Blain, Maxime Scientific Reports, Vol. 11, Issue 1 https://doi.org/10.1038/s41598-021-85694-5	journal	March 2021
Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development Imai, Masaki; Iwatsuki-Horimoto, Kiyoko; Hatta, Masato Proceedings of the National Academy of Sciences, Vol. 117, Issue 28 https://doi.org/10.1073/pnas.2009799117	journal	June 2020
Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort Néant, Nadège; Lingas, Guillaume; Le Hingrat, Quentin Proceedings of the National Academy of Sciences, Vol. 118, Issue 8 https://doi.org/10.1073/pnas.2017962118	journal	February 2021
Early Induction of Cross-Reactive CD8+ T-Cell Responses in Tonsils After Live-Attenuated Influenza Vaccination in Children Mohn, K. G-I; Brokstad, K. A.; Islam, S. The Journal of Infectious Diseases, Vol. 221, Issue 9 https://doi.org/10.1093/infdis/jiz583	journal	April 2020
The T-cell response to SARS-CoV-2: kinetic and quantitative aspects and the case for their protective role Bertoletti, Antonio; Tan, Anthony T.; Le Bert, Nina Oxford Open Immunology, Vol. 2, Issue 1 https://doi.org/10.1093/oxfimm/iqab006	journal	January 2021
A simplified model of the Human Immune System response to the COVID-19 Xavier, Maicom Peters; Reis, Ruy F.; dos Santos, Rodrigo W. 2020 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) https://doi.org/10.1109/BIBM49941.2020.9313418	conference	December 2020
UPC++: A High-Performance Communication Framework for Asynchronous Computation Bachan, John; Baden, Scott B.; Hofmeyr, Steven 2019 IEEE International Parallel and Distributed Processing Symposium (IPDPS) https://doi.org/10.1109/IPDPS.2019.00104	conference	May 2019
Potential killers exposed: tracking endogenous influenza-specific CD8 ⁺ T cells Keating, Rachael; Morris, Melissa Y.; Yue, Wen Immunology and Cell Biology, Vol. 96, Issue 10 https://doi.org/10.1111/imcb.12189	journal	August 2018
Lung morphometry by unbiased methods in emphysema: bronchial and blood vessel volume, alveolar surface area and capillary length Wiebe, Britt Marie; Laursen, Henning APMIS, Vol. 106, Issue 1-6 https://doi.org/10.1111/j.1699-0463.1998.tb01395.x	journal	January 1998
Potency and timing of antiviral therapy as determinants of duration of SARS-CoV-2 shedding and intensity of inflammatory response Goyal, Ashish; Cardozo-Ojeda, E. Fabian; Schiffer, Joshua T. Science Advances, Vol. 6, Issue 47 https://doi.org/10.1126/sciadv.abc7112	journal	October 2020
Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans Arunachalam, Prabhu S.; Wimmers, Florian; Mok, Chris Ka Pun Science, Vol. 369, Issue 6508 https://doi.org/10.1126/science.abc6261	journal	August 2020
Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus Miao, H.; Hollenbaugh, J. A.; Zand, M. S. Journal of Virology, Vol. 84, Issue 13 https://doi.org/10.1128/JVI.00266-10	journal	April 2010
Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain Schneider, Martha; Ackermann, Kerstin; Stuart, Melissa Journal of Virology, Vol. 86, Issue 18 https://doi.org/10.1128/JVI.01001-12	journal	July 2012
Estimating In Vivo Death Rates of Targets due to CD8 T-Cell-Mediated Killing Ganusov, Vitaly V.; De Boer, Rob J. Journal of Virology, Vol. 82, Issue 23 https://doi.org/10.1128/JVI.01128-08	journal	December 2008
Higher Level of Replication Efficiency of 2009 (H1N1) Pandemic Influenza Virus than Those of Seasonal and Avian Strains: Kinetics from Epithelial Cell Culture and Computational Modeling Mitchell, H.; Levin, D.; Forrest, S. Journal of Virology, Vol. 85, Issue 2 https://doi.org/10.1128/JVI.01722-10	journal	November 2010
A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2 Kim, Kwang Su; Ejima, Keisuke; Iwanami, Shoya PLOS Biology, Vol. 19, Issue 3 https://doi.org/10.1371/journal.pbio.3001128	journal	March 2021
Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search Fricke, G. Matthew; Letendre, Kenneth A.; Moses, Melanie E. PLOS Computational Biology, Vol. 12, Issue 3 https://doi.org/10.1371/journal.pcbi.1004818	journal	March 2016
A mathematical model describing the localization and spread of influenza A virus infection within the human respiratory tract Quirouette, Christian; Younis, Nada P.; Reddy, Micaela B. PLOS Computational Biology, Vol. 16, Issue 4 https://doi.org/10.1371/journal.pcbi.1007705	journal	April 2020
A modular framework for multiscale, multicellular, spatiotemporal modeling of acute primary viral infection and immune response in epithelial tissues and its application to drug therapy timing and effectiveness Sego, T. J.; Aponte-Serrano, Josua O.; Ferrari Gianlupi, Juliano PLOS Computational Biology, Vol. 16, Issue 12 https://doi.org/10.1371/journal.pcbi.1008451	journal	December 2020
Examination of Influenza Specific T Cell Responses after Influenza Virus Challenge in Individuals Vaccinated with MVA-NP+M1 Vaccine Powell, Timothy J.; Peng, Yanchun; Berthoud, Tamara K. PLoS ONE, Vol. 8, Issue 5 https://doi.org/10.1371/journal.pone.0062778	journal	May 2013
Disentangling the dynamical underpinnings of differences in SARS-CoV-2 pathology using within-host ecological models Metcalf, C. Jessica E.; Grenfell, Bryan T.; Graham, Andrea L. PLOS Pathogens, Vol. 16, Issue 12 https://doi.org/10.1371/journal.ppat.1009105	journal	December 2020
Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19 Dabisch, Paul A.; Biryukov, Jennifer; Beck, Katie PLOS Pathogens, Vol. 17, Issue 8 https://doi.org/10.1371/journal.ppat.1009865	journal	August 2021
Which Sensitivity Analysis Method Should I Use for My Agent-Based Model? ten Broeke, Guus; van Voorn, George; Ligtenberg, Arend Journal of Artificial Societies and Social Simulation, Vol. 19, Issue 1 https://doi.org/10.18564/jasss.2857	journal	January 2016
Distributed Adaptive Search in T Cells: Lessons From Ants Moses, Melanie E.; Cannon, Judy L.; Gordon, Deborah M. Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.01357	journal	June 2019
Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization Ariotti, S.; Beltman, J. B.; Borsje, R. The Journal of Immunology, Vol. 195, Issue 11 https://doi.org/10.4049/jimmunol.1500853	journal	November 2015
Evidence for transmission of COVID-19 prior to symptom onset Tindale, Lauren C.; Stockdale, Jessica E.; Coombe, Michelle eLife, Vol. 9 https://doi.org/10.7554/eLife.57149	journal	June 2020
High infectiousness immediately before COVID-19 symptom onset highlights the importance of continued contact tracing Hart, William S.; Maini, Philip K.; Thompson, Robin N. eLife, Vol. 10 https://doi.org/10.7554/eLife.65534	journal	April 2021

Similar Records

Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes

Journal Article · 2024 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:2283788

Zhang, Yue; Bharathi, Vanthana; Dokoshi, Tatsuya; +32 more

3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice

Journal Article · 2020 · Science Translational Medicine · OSTI ID:1661001

Rathnayake, Athri D.; Zheng, Jian; Kim, Yunjeong; +9 more

The kinetics of SARS-CoV-2 infection based on a human challenge study

Journal Article · 2024 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:2476565

Iyaniwura, Sarafa A.; Ribeiro, Ruy M.; Zitzmann, Carolin; +3 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
SARS-CoV-2

Title: Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

Citation Formats

References (51)

Similar Records

Related Subjects