Data-driven multi-scale mathematical modeling of SARS-CoV-2 infection reveals heterogeneity among COVID-19 patients

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 naive 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. Author summary Coronavirus disease 2019 (COVID-19) is currently destroying both lives and economies. However, patients infected with severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) usually present heterogeneous and complicated progressions, such as different incubation periods (short and long), symptoms (asymptomatic and symptomatic) and severity (mild-moderate and severe). Currently, various clinical data and experimental data are available from different countries, which has great significance for integrating different types of data to comprehensively understand the diverse disease progression in COVID-19 patients and guide individual treatment strategies. Here, we developed a multi-scale computational model to describe the dynamical process of patients infected with SARS-CoV-2, including intracellular viral dynamics, multicellular infection process, and immune responses. By combining data integration, stochastic simulation and quantitative analysis based on the multi-scale mathematical model, we addressed an important question regarding how IFN response and T cell exhaustion quantitatively affect heterogeneous progression in patients with respect to incubation periods, symptoms and severity. Furthermore, the efficacy of various therapeutic strategies for treating COVID-19 patients with different severity degrees was evaluated and validated. The computational framework in this study can also be extended to explore the dynamical process of other coronavirus infections.