Mathematical Modeling and Analysis of Factors influencing the intracellular Replication of SARS-CoV-2 and related Coronaviruses

• Applicants: Professor Dr. Lars Kaderali; Professorin Dr. Stephanie Pfänder
• Subject Area: Virology ; Bioinformatics and Theoretical Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462165342

Human infections with the endemic coronaviruses are often associated with mild, cold-like symptoms. However, in the past two decades, three highly pathogenic coronaviruses have emerged which caused severe respiratory syndromes in humans. In 2002, 2012, and 2019, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV-2 emerged, respectively, causing severe infections associated with a varied mortality in humans. SARS-CoV-2, causing the disease COVID-19, has up to now (November 2nd, 2020) infected 46,166,182 individuals, including 1,196,362 deaths (World Health Organization). To date, no efficient antiviral drug and no vaccine against SARS-CoV-2 are available, the virus thus remains a major health concern. At the same time, other pathogenic coronaviruses may emerge in the future, presenting further challenges for health and medical research.Mathematical modeling has a long history as a tool to study viral dynamics, and mathematical models have been used to describe intracellular replication dynamics, cell-to-cell infection in cell culture and tissue, viral spread within organs, organisms, and in populations. Mathematical modeling can support our understanding of interactions between the virus and the host, can be useful to characterize infection dynamics at the level of cells and cell populations as well as patients, and can support the development of antiviral treatment strategies.This is what the present project proposal addresses: Building on our prior work on modeling virus-host interactions and integrating newly acquired kinetic data, we will develop a dynamic mathematical model of the intracellular processes associated with SARS-CoV-2 infection, replication and assembly. The model will take relevant molecular details into account and will provide a quantitative, dynamic picture of the full intracellular virus lifecycle and key interactions with the host cell, in particular the innate immune response. This model will enable us to study viral replication strategies, will provide clues as to what factors determine the outcome of the race between viral replication and antiviral immune response, and we will employ mathematical model analysis to evaluate the effect of different potential antiviral intervention strategies. We will take the currently pandemic SARS-CoV-2 virus as a model system, but the developed mathematical model can be readily adapted to other emerging coronaviruses, and will become a valuable tool to understand the intracellular dynamics of coronavirus infection and its mutual interplay with the host cell’s innate immune response.To achieve these ambitious goals, a computational modeler with well over a decade experience in modeling viral replication and one of the leading young virological specialists on coronaviruses in Germany have joined forces in the proposed research project, and will closely collaborate to achieve the project objectives.

• DFG Programme: Research Grants