Modeling Within-Host Dynamics of SARS-CoV-2 Infection: A Case Study in Ferrets

Vaidya, Naveen K.; Bloomquist, Angelica; Perelson, Alan S.

doi:10.3390/v13081635

Modeling Within-Host Dynamics of SARS-CoV-2 Infection: A Case Study in Ferrets

Journal Article · Wed Aug 18 00:00:00 EDT 2021 · Viruses

DOI:https://doi.org/10.3390/v13081635· OSTI ID:1825455

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San Diego State Univ., CA (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

The pre-clinical development of antiviral agents involves experimental trials in animals and ferrets as an animal model for the study of SARS-CoV-2. Here, we used mathematical models and experimental data to characterize the within-host infection dynamics of SARS-CoV-2 in ferrets. We also performed a global sensitivity analysis of model parameters impacting the characteristics of the viral infection. We provide estimates of the viral dynamic parameters in ferrets, such as the infection rate, the virus production rate, the infectious virus proportion, the infected cell death rate, the virus clearance rate, as well as other related characteristics, including the basic reproduction number, pre-peak infectious viral growth rate, post-peak infectious viral decay rate, pre-peak infectious viral doubling time, post-peak infectious virus half-life, and the target cell loss in the respiratory tract. These parameters and indices are not significantly different between animals infected with viral strains isolated from the environment and isolated from human hosts, indicating a potential for transmission from fomites. While the infection period in ferrets is relatively short, the similarity observed between our results and previous results in humans supports that ferrets can be an appropriate animal model for SARS-CoV-2 dynamics-related studies, and our estimates provide helpful information for such studies.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1825455

Report Number(s):: LA-UR--21-25832

Journal Information:: Viruses, Journal Name: Viruses Journal Issue: 8 Vol. 13; ISSN 1999-4915

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

References (58)

Genetic Variants of SARS-CoV-2—What Do They Mean? Lauring, Adam S.; Hodcroft, Emma B. JAMA, Vol. 325, Issue 6 https://doi.org/10.1001/jama.2020.27124	journal	February 2021
Mechanistic Modeling of SARS‐CoV‐2 and Other Infectious Diseases and the Effects of Therapeutics Perelson, Alan S.; Ke, Ruian Clinical Pharmacology & Therapeutics, Vol. 109, Issue 4 https://doi.org/10.1002/cpt.2160	journal	March 2021
Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load Gonçalves, Antonio; Bertrand, Julie; Ke, Ruian CPT: Pharmacometrics & Systems Pharmacology, Vol. 9, Issue 9 https://doi.org/10.1002/psp4.12543	journal	August 2020
The HIV-1 Vaccine Race Ho, David D.; Huang, Yaoxing Cell, Vol. 110, Issue 2 https://doi.org/10.1016/S0092-8674(02)00832-2	journal	July 2002
Viral load of SARS-CoV-2 in clinical samples Pan, Yang; Zhang, Daitao; Yang, Peng The Lancet Infectious Diseases, Vol. 20, Issue 4 https://doi.org/10.1016/S1473-3099(20)30113-4	journal	April 2020
Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant Ryu, Dong-Kyun; Song, Rina; Kim, Minsoo Biochemical and Biophysical Research Communications, Vol. 566 https://doi.org/10.1016/j.bbrc.2021.06.016	journal	August 2021
SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract Hou, Yixuan J.; Okuda, Kenichi; Edwards, Caitlin E. Cell, Vol. 182, Issue 2 https://doi.org/10.1016/j.cell.2020.05.042	journal	July 2020
Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model Proud, Pamela C.; Tsitoura, Daphne; Watson, Robert J. EBioMedicine, Vol. 63 https://doi.org/10.1016/j.ebiom.2020.103153	journal	January 2021
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
Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques Kumar, Rakesh; Orsoni, Suheydi; Norman, Lisa Virology, Vol. 354, Issue 1 https://doi.org/10.1016/j.virol.2006.06.020	journal	October 2006
Dynamics of lentiviral infection in vivo in the absence of adaptive immune responses Schwartz, Elissa J.; Vaidya, Naveen K.; Dorman, Karin S. Virology, Vol. 513 https://doi.org/10.1016/j.virol.2017.09.023	journal	January 2018
Review of infective dose, routes of transmission and outcome of COVID-19 caused by the SARS-COV-2: comparison with other respiratory viruses Karimzadeh, Sedighe; Bhopal, Raj; Nguyen Tien, Huy Epidemiology and Infection, Vol. 149 https://doi.org/10.1017/S0950268821000790	journal	January 2021
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 ACS Pharmacology & Translational Science, Vol. 4, Issue 1 https://doi.org/10.1021/acsptsci.0c00183	journal	December 2020
SARS virus infection of cats and ferrets Martina, Byron E. E.; Haagmans, Bart L.; Kuiken, Thijs Nature, Vol. 425, Issue 6961 https://doi.org/10.1038/425915a	journal	October 2003
H7N9 virulent mutants detected in chickens in China pose an increased threat to humans Shi, Jianzhong; Deng, Guohua; Kong, Huihui Cell Research, Vol. 27, Issue 12 https://doi.org/10.1038/cr.2017.129	journal	October 2017
The Ferret: An Animal Model to Study Influenza Virus Maher, John A.; DeStefano, Joanne Lab Animal, Vol. 33, Issue 9 https://doi.org/10.1038/laban1004-50	journal	October 2004
Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets Imai, Masaki; Watanabe, Tokiko; Hatta, Masato Nature, Vol. 486, Issue 7403 https://doi.org/10.1038/nature10831	journal	May 2012
Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity Ryan, Kathryn A.; Bewley, Kevin R.; Fotheringham, Susan A. Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-020-20439-y	journal	January 2021
A new coronavirus associated with human respiratory disease in China Wu, Fan; Zhao, Su; Yu, Bin Nature, Vol. 579, Issue 7798 https://doi.org/10.1038/s41586-020-2008-3	journal	February 2020
Virological assessment of hospitalized patients with COVID-2019 Wölfel, Roman; Corman, Victor M.; Guggemos, Wolfgang Nature, Vol. 581, Issue 7809 https://doi.org/10.1038/s41586-020-2196-x	journal	April 2020
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes Sungnak, Waradon; Huang, Ni; Bécavin, Christophe Nature Medicine, Vol. 26, Issue 5 https://doi.org/10.1038/s41591-020-0868-6	journal	April 2020
Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics Mutua, Jones M.; Perelson, Alan S.; Kumar, Anil Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-41751-8	journal	April 2019
SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients Zou, Lirong; Ruan, Feng; Huang, Mingxing New England Journal of Medicine, Vol. 382, Issue 12 https://doi.org/10.1056/NEJMc2001737	journal	March 2020
Emergence of a Highly Fit SARS-CoV-2 Variant Baric, Ralph S. New England Journal of Medicine, Vol. 383, Issue 27 https://doi.org/10.1056/NEJMcibr2032888	journal	December 2020
The role of cells refractory to productive infection in acute hepatitis B viral dynamics Ciupe, S. M.; Ribeiro, R. M.; Nelson, P. W. Proceedings of the National Academy of Sciences, Vol. 104, Issue 12 https://doi.org/10.1073/pnas.0603626104	journal	March 2007
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
The total number and mass of SARS-CoV-2 virions Sender, Ron; Bar-On, Yinon M.; Gleizer, Shmuel Proceedings of the National Academy of Sciences, Vol. 118, Issue 25 https://doi.org/10.1073/pnas.2024815118	journal	June 2021
Virus dynamics and drug therapy Bonhoeffer, S.; May, R. M.; Shaw, G. M. Proceedings of the National Academy of Sciences, Vol. 94, Issue 13 https://doi.org/10.1073/pnas.94.13.6971	journal	June 1997
Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan Chan, Jasper Fuk-Woo; Kok, Kin-Hang; Zhu, Zheng Emerging Microbes & Infections, Vol. 9, Issue 1 https://doi.org/10.1080/22221751.2020.1719902	journal	January 2020
Early events in hepatitis B infection: the role of inoculum dose Ciupe, Stanca M.; Vaidya, Naveen K.; Forde, Jonathan E. Proceedings of the Royal Society B: Biological Sciences, Vol. 288, Issue 1944 https://doi.org/10.1098/rspb.2020.2715	journal	February 2021
SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients Klimstra, William B.; Tilston-Lunel, Natasha L.; Nambulli, Sham Journal of General Virology https://doi.org/10.1099/jgv.0.001481	journal	August 2020
Hamster and ferret experimental infection with intranasal low dose of a single strain of SARS-CoV-2 Monchatre-Leroy, Elodie; Lesellier, Sandrine; Wasniewski, Marine Journal of General Virology, Vol. 102, Issue 3 https://doi.org/10.1099/jgv.0.001567	journal	March 2021
Pathogenesis of emerging avian influenza viruses in mammals and the host innate immune response Maines, Taronna R.; Szretter, Kristy J.; Perrone, Lucy Immunological Reviews, Vol. 225, Issue 1 https://doi.org/10.1111/j.1600-065X.2008.00690.x	journal	October 2008
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
Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets Herfst, S.; Schrauwen, E. J. A.; Linster, M. Science, Vol. 336, Issue 6088 https://doi.org/10.1126/science.1213362	journal	June 2012
H7N9 Influenza Viruses Are Transmissible in Ferrets by Respiratory Droplet Zhang, Qianyi; Shi, Jianzhong; Deng, Guohua Science, Vol. 341, Issue 6144 https://doi.org/10.1126/science.1240532	journal	July 2013
Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS–coronavirus 2 Shi, Jianzhong; Wen, Zhiyuan; Zhong, Gongxun Science, Vol. 368, Issue 6494 https://doi.org/10.1126/science.abb7015	journal	May 2020
The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection Asabe, S.; Wieland, S. F.; Chattopadhyay, P. K. Journal of Virology, Vol. 83, Issue 19 https://doi.org/10.1128/JVI.00867-09	journal	July 2009
Kinetics of Influenza A Virus Infection in Humans Baccam, P.; Beauchemin, C.; Macken, C. A. Journal of Virology, Vol. 80, Issue 15 https://doi.org/10.1128/JVI.01623-05	journal	July 2006
Viral Dynamics during Primary Simian Immunodeficiency Virus Infection: Effect of Time-Dependent Virus Infectivity Vaidya, N. K.; Ribeiro, R. M.; Miller, C. J. Journal of Virology, Vol. 84, Issue 9 https://doi.org/10.1128/JVI.02284-09	journal	February 2010
High Specific Infectivity of Plasma Virus from the Pre-Ramp-Up and Ramp-Up Stages of Acute Simian Immunodeficiency Virus Infection Ma, Z. -M.; Stone, M.; Piatak, M. Journal of Virology, Vol. 83, Issue 7 https://doi.org/10.1128/JVI.02423-08	journal	January 2009
Modulation by Morphine of Viral Set Point in Rhesus Macaques Infected with Simian Immunodeficiency Virus and Simian-Human Immunodeficiency Virus Kumar, R.; Torres, C.; Yamamura, Y. Journal of Virology, Vol. 78, Issue 20 https://doi.org/10.1128/JVI.78.20.11425-11428.2004	journal	September 2004
Transcriptional and posttranscriptional regulation of exogenous human beta interferon gene in simian cells defective in interferon synthesis. Mosca, J. D.; Pitha, P. M. Molecular and Cellular Biology, Vol. 6, Issue 6 https://doi.org/10.1128/MCB.6.6.2279	journal	June 1986
Defectiveness of Interferon Production and of Rubella Virus Interference in a Line of African Green Monkey Kidney Cells (Vero) Desmyter, Jan; Melnick, Joseph L.; Rawls, William E. Journal of Virology, Vol. 2, Issue 10 https://doi.org/10.1128/jvi.2.10.955-961.1968	journal	October 1968
Human Clade 2.3.4.4 A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers and Does Not Transmit via the Airborne Route between Ferrets Herfst, Sander; Mok, Chris K. P.; van den Brand, Judith M. A. mSphere, Vol. 3, Issue 1 https://doi.org/10.1128/mSphere.00405-17	journal	January 2018
On Identifiability of Nonlinear ODE Models and Applications in Viral Dynamics Miao, Hongyu; Xia, Xiaohua; Perelson, Alan S. SIAM Review, Vol. 53, Issue 1 https://doi.org/10.1137/090757009	journal	January 2011
Pathology of Experimental SARS Coronavirus Infection in Cats and Ferrets van den Brand, J. M. A.; Haagmans, B. L.; Leijten, L. Veterinary Pathology, Vol. 45, Issue 4 https://doi.org/10.1354/vp.45-4-551	journal	July 2008
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
Modeling Within-Host Dynamics of Influenza Virus Infection Including Immune Responses Pawelek, Kasia A.; Huynh, Giao T.; Quinlivan, Michelle PLoS Computational Biology, Vol. 8, Issue 6 https://doi.org/10.1371/journal.pcbi.1002588	journal	June 2012
Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics Vaidya, Naveen K.; Ribeiro, Ruy M.; Perelson, Alan S. PLOS Computational Biology, Vol. 12, Issue 9 https://doi.org/10.1371/journal.pcbi.1005127	journal	September 2016
Success of prophylactic antiviral therapy for SARS-CoV-2: Predicted critical efficacies and impact of different drug-specific mechanisms of action Czuppon, Peter; Débarre, Florence; Gonçalves, Antonio PLOS Computational Biology, Vol. 17, Issue 3 https://doi.org/10.1371/journal.pcbi.1008752	journal	March 2021
SARS-CoV-2 viral dynamics in non-human primates Gonçalves, Antonio; Maisonnasse, Pauline; Donati, Flora PLOS Computational Biology, Vol. 17, Issue 3 https://doi.org/10.1371/journal.pcbi.1008785	journal	March 2021
Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials: A modeling study Iwanami, Shoya; Ejima, Keisuke; Kim, Kwang Su PLOS Medicine, Vol. 18, Issue 7 https://doi.org/10.1371/journal.pmed.1003660	journal	July 2021
Viral Load Kinetics of SARS-CoV-2 Infection in First Two Patients in Korea Kim, Jin Yong; Ko, Jae-Hoon; Kim, Yeonjae Journal of Korean Medical Science, Vol. 35, Issue 7 https://doi.org/10.3346/jkms.2020.35.e86	journal	January 2020
Correlation Between Anti-gp41 Antibodies and Virus Infectivity Decay During Primary HIV-1 Infection Vaidya, Naveen K.; Ribeiro, Ruy M.; Liu, Pinghuang Frontiers in Microbiology, Vol. 9 https://doi.org/10.3389/fmicb.2018.01326	journal	June 2018
Animal Models Used in Hepatitis C Virus Research Berggren, Keith A.; Suzuki, Saori; Ploss, Alexander International Journal of Molecular Sciences, Vol. 21, Issue 11 https://doi.org/10.3390/ijms21113869	journal	May 2020
Endogenously Produced SARS-CoV-2 Specific IgG Antibodies May Have a Limited Impact on Clearing Nasal Shedding of Virus during Primary Infection in Humans Yang, Shuyi; Jerome, Keith R.; Greninger, Alexander L. Viruses, Vol. 13, Issue 3 https://doi.org/10.3390/v13030516	journal	March 2021
Ferrets as a Novel Animal Model for Studying Human Respiratory Syncytial Virus Infections in Immunocompetent and Immunocompromised Hosts Stittelaar, Koert; de Waal, Leon; van Amerongen, Geert Viruses, Vol. 8, Issue 6 https://doi.org/10.3390/v8060168	journal	June 2016

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59 BASIC BIOLOGICAL SCIENCES
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viral dynamics
within-host modeling

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