RAPID: Identifying the Role of Mucus in COVID-19 Pathogenesis

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In December 2019, a novel coronavirus (SARS-CoV-2) was identified to cause COVID-19, a highly infectious respiratory disease that has rapidly spread around the world. Cases are on the rise in the United States, and hospitals are in danger of being overwhelmed by severe cases, but there is currently no specific treatment. Improving our understanding of virus transmission and disease progression is critical to identifying the preventative measures and therapeutic options needed to address this pandemic. This project focuses on mucus, a critical host factor, and its role in two aspects of the infection: how the virus reaches and penetrates the epithelium, and how mucus properties relate to symptom severity. This project uses a two-pronged approach to identify the role of mucus in COVID-19 pathogenesis, which will begin to reveal critical steps underlying infection through the mucus barrier. Aim 1 shall identify the mechanisms by which SARS-CoV-2 binds to and transports through mucus, which will establish an understanding of binding between SARS-CoV-2 surface proteins and native human mucins and how these binding interactions affect virus transport across the mucus barrier. Aim 2 shall identify structural, biochemical, and virus binding properties of nasal mucus that distinguish asymptomatic from severe COVID-19 patients, leading to the identification of mucus structure (degradation, mucin concentration, degree of crosslinking) and glycosylation profiles in clinical nasal mucus samples from asymptomatic and severe COVID-19 patients to identify how these groups differ and whether these properties impact virus mobility and susceptibility to infection.Virus transport will be assessed by tracking the motion of fluorescent SARS-CoV-2-like particles embedded within native mucus and purified human mucins under different conditions and treatment with specific glycosidases. Effects of mucus permeability on virus transport will be assessed using microfluidics-based live cell fluorescence microscopy. This project will advance the understanding of a poorly understood transport phenomenon of virus particles through the mucus barrier. This knowledge will advance the fundamental understanding of the role of mucus in COVID-19 pathogenesis and provide the foundation for therapeutic targets. With a carefully-chosen collaboration between MIT and BU, the data obtained within this project will provide essential results needed for the generation of cutting-edge models for selective, facilitated passage of SARS-CoV-2 through the mucus barrier. This project will help the development of processes and actions that are needed to combat the COVID-19 pandemic.This grant is being awarded using funds made available by the Coronavirus Aid, Relief, and Economic Security (CARES) Act supplement allocated to MPS.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.