Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model.
Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model.
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DOI：
10.1021/acsptsci.0c00183
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发表时间：
2021-02-12
影响因子：
--
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Dogra P;Ruiz-Ramírez J;Sinha K;Butner JD;Peláez MJ;Rawat M;Yellepeddi VK;Pasqualini R;Arap W;Sostman HD;Cristini V;Wang Z
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是一种引起广泛关注的病原体。控制这种疾病的努力只取得了轻微的成功，在开发出有效的预防措施（如疫苗）之前，这种疾病可能会继续造成过多的死亡。为了制定疾病管理策略，需要更好地了解SARS-CoV-2的发病机制和人群对感染的易感性。为此，数学建模可以提供一个强大的计算机工具来了解COVID-19的病理生理学和SARS-CoV-2的体内动力学。引导ACE 2-tropism（ACE 2受体依赖性感染）的病毒，并通过将细胞规模的病毒动力学和先天性和适应性免疫反应，我们已经开发了一个多尺度的机制模型，用于模拟病毒载量分布的时间依赖性演变的易感器官的身体（呼吸道，肠道，肝脏，脾脏，心脏，肾脏和大脑）。在体内和临床数据的参数量化之后，我们使用该模型来模拟具有不同程度免疫状态受损的虚拟患者中的病毒载量进展。此外，我们通过敏感性分析对模型参数进行了排序，以了解生理因素和基础条件对病毒载量动态的影响。模拟抗病毒药物治疗、干扰素治疗及其联合治疗对SARS-CoV-2病毒载量动力学的影响。该模型揭示了先天免疫（特别是干扰素和常驻巨噬细胞）在控制病毒载量方面的主导作用，以及感染后开始治疗时时机的重要性。
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.
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影响因子：
16.6
作者：
Dogra P;Adolphi NL;Wang Z;Lin YS;Butler KS;Durfee PN;Croissant JG;Noureddine A;Coker EN;Bearer EL;Cristini V;Brinker CJ
通讯作者：
Brinker CJ
影响因子：
6.4
作者：
Collin M;Bigley V
通讯作者：
Bigley V
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
影响因子：
4.6
作者：
Brocato TA;Coker EN;Durfee PN;Lin YS;Townson J;Wyckoff EF;Cristini V;Brinker CJ;Wang Z
通讯作者：
Wang Z
影响因子：
1.7
作者：
Bianconi, Eva;Piovesan, Allison;Canaider, Silvia
通讯作者：
Canaider, Silvia