Wilen Lab

PROJECTS

COVID-19 pathogenesis and therapeutics

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The virus SARS-CoV2 is the cause of the current global pandemic resulting in more than 2,000,000 infections and more than 150,000 deaths worldwide.  To identify novel drug targets and therapeutics, we are currently performing genome-wide CRISPR screens and high-throughput drug screens with SARS-Cov2. We utilize SARS-CoV2 reporter viruses in the BSL2 laborattory and fully infectious wild type SARS-CoV2 in the BSL3 laboratory. To discover how SARS-Cov2 causes disease, we utilize single-cell RNA sequencing of infected primary human airway cells and tissues in the BSL3. Finally, we test drug and vaccine targets in SARS-CoV2 susceptible mouse models.

Viral Immune Evasion

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Immunity against human norovirus is transient and inadequate. We want to discover why this is to develop a vaccine that induces long-term protective immunity.  Using a mouse model of norovirus, we discovered that the mouse norovrus infects a rare epithelial cell called tuft cells. Tuft cells are interesting because they sense and respond to worm and parasite infection. Worm and parasite infection also exacerbate norovirus pathogenesis. We are interested in how tuft cell tropism regulates viral pathogenesis. Specifically, we want to identify how infected tuft cells escape the host innate and adaptive immune responses. We are also interested in understanding the mechanisms by which the type II immune response initiated by worm infection increases viral pathogenesis. Elucidating the mechanisms of norovirus immune interactions has important implications for our understanding of norovirus transmission and vaccine design.

Norovirus Pathogenesis

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Human norovirus causes a gastrointestinal illness characterized by profuse diarrhea and vomiting. While norovirus outbreaks are commonly linked to cruise ships, the disease burden is greatest in young children in the developing world, which represent the majority of the 200,000 deaths per year due to this poorly understood virus. There are currently no medications or vaccines to treat or prevent human norovirus infection. This is, in part, a result of our limited understanding about how norovirus establishes infection and causes disease. For instance, it is unknown what types of cells norovirus infects, how it infects a given cell, how it spreads between cells, and how it establishes persistent infection in some people. We use mouse models and stem-cell derived intestinal enteroids to study norovirus pathogenesis in vitro and in vivo.

Tuft Cell Biology

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Tuft cells are named after their long tuft of microvilli that protrudes into the intestinal lumen. They are rare chemosensory cells that sense and respond to small molecules and microorganisms within the intestines.  Most notably, they secrete the cytokine IL-25 in response to worm infection which initiates a type II immune response to combat worm infection. Tuft cell link the enteric nervous system, the immune system, and intestinal epithelium as they require neuronal innervation for survival, and are critical to effectively clear intestinal worms and parasites. However, much about their function, including their role in viral infection and immunity, remains a mystery.