{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:54:01Z","timestamp":1780109641144,"version":"3.54.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009587","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000}}],"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["no. 11831015"],"award-info":[{"award-number":["no. 11831015"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["no. 11831015"],"award-info":[{"award-number":["no. 11831015"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["no. 2019CFA007"],"award-info":[{"award-number":["no. 2019CFA007"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Patients with coronavirus disease 2019 (COVID-19) often exhibit diverse disease progressions associated with various infectious ability, symptoms, and clinical treatments. To systematically and thoroughly understand the heterogeneous progression of COVID-19, we developed a multi-scale computational model to quantitatively understand the heterogeneous progression of COVID-19 patients infected with severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2). The model consists of intracellular viral dynamics, multicellular infection process, and immune responses, and was formulated using a combination of differential equations and stochastic modeling. By integrating multi-source clinical data with model analysis, we quantified individual heterogeneity using two indexes, i.e., the ratio of infected cells and incubation period. Specifically, our simulations revealed that increasing the host antiviral state or virus induced type I interferon (IFN) production rate can prolong the incubation period and postpone the transition from asymptomatic to symptomatic outcomes. We further identified the threshold dynamics of T cell exhaustion in the transition between mild-moderate and severe symptoms, and that patients with severe symptoms exhibited a lack of na\u00efve T cells at a late stage. In addition, we quantified the efficacy of treating COVID-19 patients and investigated the effects of various therapeutic strategies. Simulations results suggested that single antiviral therapy is sufficient for moderate patients, while combination therapies and prevention of T cell exhaustion are needed for severe patients. These results highlight the critical roles of IFN and T cell responses in regulating the stage transition during COVID-19 progression. Our study reveals a quantitative relationship underpinning the heterogeneity of transition stage during COVID-19 progression and can provide a potential guidance for personalized therapy in COVID-19 patients.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009587","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T18:34:54Z","timestamp":1637778894000},"page":"e1009587","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["Data-driven multi-scale mathematical modeling of SARS-CoV-2 infection reveals heterogeneity among COVID-19 patients"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2694-9559","authenticated-orcid":true,"given":"Shun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3918-0737","authenticated-orcid":true,"given":"Mengqian","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zishu","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2670-6760","authenticated-orcid":true,"given":"Jinzhi","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-0764","authenticated-orcid":true,"given":"Xiufen","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"issue":"10223","key":"pcbi.1009587.ref001","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"C Huang","year":"2020","journal-title":"The Lancet"},{"issue":"4","key":"pcbi.1009587.ref002","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Z Xu","year":"2020","journal-title":"The Lancet Respiratory Medicine"},{"issue":"4","key":"pcbi.1009587.ref003","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/ped4.12228","article-title":"Cell-mediated immunity to SARS-CoV-2","volume":"4","author":"X Wang","year":"2020","journal-title":"Pediatric Investigation"},{"issue":"15","key":"pcbi.1009587.ref004","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China","volume":"71","author":"C Qin","year":"2020","journal-title":"Clinical Infectious Diseases"},{"issue":"3","key":"pcbi.1009587.ref005","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/imm.13223","article-title":"Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China","volume":"160","author":"M Tan","year":"2020","journal-title":"Immunology"},{"issue":"3","key":"pcbi.1009587.ref006","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.jfma.2020.02.009","article-title":"SARS-CoV-2 infection in children: Transmission dynamics and clinical characteristics","volume":"119","author":"Q Cao","year":"2020","journal-title":"Journal of the Formosan Medical Association"},{"issue":"3","key":"pcbi.1009587.ref007","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jmii.2020.02.011","article-title":"Are children less susceptible to COVID-19?","volume":"53","author":"PI Lee","year":"2020","journal-title":"Journal of Microbiology, Immunology and Infection"},{"issue":"5","key":"pcbi.1009587.ref008","first-page":"706","article-title":"Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China","volume":"63","author":"Z Hu","year":"2020","journal-title":"medRxiv"},{"issue":"1","key":"pcbi.1009587.ref009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-020-00306-4","article-title":"Type I IFN deficiency: an immunological characteristic of severe COVID-19 patients","volume":"5","author":"Z Wang","year":"2020","journal-title":"Signal Transduction and Targeted Therapy"},{"issue":"10","key":"pcbi.1009587.ref010","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1056\/NEJMc2001468","article-title":"Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany","volume":"382","author":"C Rothe","year":"2020","journal-title":"New England Journal of Medicine"},{"issue":"2","key":"pcbi.1009587.ref011","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. 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