Of Viruses and Barriers

Emerging and re-emerging viruses pose some of the greatest threats to human health. These threats are epitomized by the mosquito-transmitted flaviviruses such as dengue virus, with over half the world’s population at risk of infection, and SARS-CoV-2, the causative agent of the devastating and ongoing COVID-19 pandemic. We need novel strategies to target multiple viruses given our current challenges in developing efficacious therapeutics and vaccines and our inability to predict future viral epidemics. Our lab aims to identify and characterize general principles of viral pathogenesis common to multiple viruses to identify new targets for vaccines and therapeutics. We are particularly focused on host-virus interactions at the interface of physiological barriers like the endothelium or epithelium, since virtually all viruses must traverse these barriers to establish a productive infection and/or transmit to subsequent hosts. Based on this commonality across viruses, we hypothesize that disrupting the capacity of viruses to break through these barriers is a viable strategy to block pathogenesis for a broad range of viruses. The research in our lab addresses this central hypothesis with projects falling into four aims:

1. How do viruses disrupt host barriers?

Our previous work has explored how flaviviruses (dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses) and coronaviruses (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) trigger barrier dysfunction. Our work has shown that soluble viral proteins, termed “viral toxins,” interact with barrier cells and trigger transient barrier dysfunction, but we still have an incomplete understanding of how viral toxins trigger barrier dysfunction. We are defining host glycans and proteins required for this process. We are also characterizing the molecular determinants within the NS1 and S glycoproteins critical for interacting with barrier cells. Discovering new viral toxins from diverse viral families is also a major priority for our lab. 

2. How does virus-triggered barrier dysfunction impact virus infection?

Virus-triggered barrier dysfunction promotes viral pathogenesis, but how this impacts the overall viral lifecycle is unclear. We hypothesize that viruses evolved the capacity to trigger barrier dysfunction in order to promote dissemination within a host and transmission to new hosts. In the case of dengue virus, we have shown that NS1-triggered leak promotes dissemination of the virus from the blood and into distal organs. For SARS-CoV-2, we have shown that the glycocalyx layer on barrier cells protects against infection, and that Spike-triggered break down of this barrier promotes viral infection. Despite some preliminary data supporting these hypotheses, our understanding of the impact of leak on virus infection is far from complete. A central goal of our lab is to establish new in vivo models to test the role of leak in virus infection. 

3. Can the host defend against virus-triggered barrier dysfunction?

Viruses and their hosts are locked in an evolutionary arms race. The virus is trying to evolve strategies to overcome host immunity and establish a replicative niche. The host is trying to detect and clear the infecting virus. We hypothesize that if the purpose of viral toxins is to enhance infection of target cells and promote virus dissemination, then the host likely has evolved strategies to overcome virus-triggered leak. Currently, no host defense strategies are known and we aim to discover and characterize these putative defense pathways. 

4. Can we develop therapeutics to block virus-triggered barrier dysfunction?

Current antiviral strategies involve targeting components of the viral replication machinery (e.g. polymerases and proteases) or surface glycoproteins. A limitation of this strategy is that these antivirals are specific to a given virus (or virus family) and place heavy selective pressure on the virus, resulting in the evolution of drug-resistant viral variants. We propose to develop a new class of therapeutics blocking virus-triggered leak. We hypothesize that this strategy will place less selective pressure on a virus because it targets viral pathogenesis and not the virus lifecycle directly. Our investigation of the mechanisms of virus-triggered barrier dysfunction will reveal new targets for therapeutic intervention that would not emerge from traditional antiviral drug screens.