What? The COVID-19 pandemic has raised fundamental questions related to SARS-CoV-2 replication and spread in cells and tissues. Cellular glycans known as heparan sulfate acts as a receptor for SARS-CoV-2 attachment and infection. The dependence on heparan sulfate, however, creates a conundrum for the virus since progeny virus exiting the infected cell needs to escape the cell surface heparan sulfate in order to spread and sustain infection. Many viruses that use glycans as attachment factors produce enzymes that can degrade these factors and facilitate the release of progeny virus, but to date, no such factors have been found for SARS-CoV-2. With this project we aim to explore the putative role of host-encoded heparanase in the release and spread of SARS-CoV-2. Why? The COVID-19 pandemic has rapidly swept across the globe, causing morbidity 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 infects cells and spreads. Exploring the putative role of heparanase as an endogenous shedding factor of SARS-CoV-2 may show to provide crucial mechanistic insights into the host-pathogen interaction of the disease. How? The project will be conducted at Professor Jeffrey Esko's lab at the University of California, San Diego, School of Medicine, USA. This lab made the initial discovery of heparan sulfate as a receptor for SARS-CoV-2 making it the ideal place to carry out this project as they have the experimental platforms and knowledge needed to conduct these studies. We will here explore the impact of host-encoded heparanases in infection and spread of the virus in cell culture and in human lung tissues using state-of-the-art CRISPR/Cas9 gene editing, enzymatic analyses, and histochemistry methodologies.