The COVID-19 pandemic is rapidly spreading, causing severe illness and death, as well as widespread disruption to all aspects of society. Thus, there is an urgent need to understand how the SARS-CoV-2 virus, the causative agent of COVID-19, causes infection. This is the focus of this project. The virus first gains access through the upper airways through aerosols or through contact with contaminated materials. The actual infection process involves contact of the virus with the surface of the cells lining the airways. This surface contains various types of glycans or polysaccharides, which are strings of different sugars connected to each other and to proteins and fats that surround the airway cells. First contact with glycans subsequently leads to virus entry into the cell. Very little is known about these glycans and how SARS-CoV-2 exploits them as a portal of entry. This research addresses this fundamental problem. The viral spike protein will be isolated, engineered and presented in a way that resembles its disposition on the virus. Its interaction with glycans found in the airways will be studies and the impact on binding of other glycans that are part of the spike protein itself will be analyzed. Results will define structurally how the virus makes first contact and subsequently invades the airway cells, providing increased knowledge about understanding of SARS-CoV-2 replication. In addition to increasing knowledge about SARS-CoV-2 biology, this proposal also supports the training of a post-doctoral fellow, broadening participation in STEM.

SARS-CoV-2 infects airway epithelial cells by interaction of the viral envelope spike (S) protein with the host cell receptor ACE2. Prior to their integration, viruses first encounter the thick glycocalyx of glycans and glycoconjugates surrounding all cells and in mucus. Most viruses use glycans as attachment factors prior to engagement with their protein receptors. Data show that SARS-CoV-2 spike protein binding to lung epithelial cells depends on cellular heparan sulfate, and that heparan sulfate may be acting as a coreceptor for ACE2. This project will characterize the interaction between the SARS-CoV-2 spike protein and host cell heparan sulfate by determining how the composition of heparan sulfate affects spike protein binding; by mapping the binding site in spike protein for heparan sulfate; and by examining the impact of altering spike protein glycans in the proximity of the binding site for heparan sulfate. The approach consists of recombinant engineering of the ectodomain of spike protein and the receptor binding domain of ACE2, binding studies with cell lines with altered heparan sulfate, mapping the heparan sulfate binding site by mutation of key amino acid residues, and reconstitution of spike protein into a pseudovirus particle to study its interaction with heparan sulfate and ACE2. This information is urgently needed to understand mechanistically host-virus interaction underlying infection by SARS-CoV-2. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, 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.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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Joanna Shisler
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University of California San Diego
La Jolla
United States
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