David Rockcliffe
$200,000
University of Wisconsin-Madison
Wisconsin
Biological Sciences (BIO)
With the zoonotic spillover of coronavirus into humans and the rapid emergence of coronavirus disease (COVID-19), humanity faces its first global pandemic in more than a century. Current molecular, cellular and animal studies of the infectious agent, SARS-CoV-2, use purified virus stocks that ignore a more likely scenario which is that the natural infection spreads as a mixture of active and defective virus strains. This project is developing mathematical models and wet-lab experiments on human coronaviruses that highlight how ecological interactions between such strains and their host cells critically impact the dynamics of virus growth, spread and ultimately their ability to cause disease. The developed models account for the presence of defective virus strains. The broader impact of the results of this project would guide clinical and front-line researchers with direct access to patients, in exploring broader and deeper measures of the infection dynamics and in applying novel therapies. The project has potential to significantly impact the development of strategies that mitigate the pandemic. This project develops mathematical models and performs wet-lab experiments on human coronaviruses. The outcome will highlight how ecological interactions between strains and their host cells could critically impact the dynamics of virus growth, spread and ultimately their ability to cause disease. The project goals are to: (i) extract essential mechanisms and parameters of coronavirus intracellular growth from the literature, (ii) build mathematical models that account for the kinetics of viral entry, gene expression, genome replication and particle assembly in the absence and presence of defective interfering (DI) particles, and (iii) implement wet-lab experiments to demonstrate the emergence of DI particles from coronavirus cultures, activation immune cytokine signaling, and validate the intracellular kinetic models. This RAPID award is made by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biology, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.