Unravelling early pathogenesis of pandemic and epidemic viruses Infection and viral dissemination at barrier tissues

Our bodies are covered by barrier tissues like the skin and mucosal surfaces of the nose, genital tract and intestines. These tissues constitute the interface of the human host and the environment and contain immune cells that prevent harmful pathogens to enter the body and cause disease. Dendritic cells (DCs) and Langerhans cells (LCs) are preferentially stationed at barrier tissues where they act as a first line of defense that is crucial to prevent infection and limit disease exacerbation. However, these cells can also be corrupted by viruses to invade the host and get disseminated to other tissues where the virus can infect additional target cells. In this thesis, we describe the interactions of four different viruses: Zika virus, SARS-CoV-2, HIV-1 and Hepatitis C virus (HCV) with cells located at human barrier tissues. We identify Heparan sulfate proteoglycans (HSPGs) and C-type lectin receptors as important receptors for virus binding and infection. Since barrier tissues are the first to encounter pathogenic viruses, they also present attractive targets for infection prevention. We show that low molecular weight heparins (LMWHs) block binding of viruses like SARS-CoV-2, by preventing interactions with HSPGs on the cell surface of epithelial cells and DC subsets, thus preventing infection as well as viral dissemination. Importantly, when applying these LMWHs directly to the nasal mucosa of healthy participants, SARS-CoV-2 binding is inhibited, suggesting them as interesting therapeutics against respiratory viruses.