Wilen Lab

PROJECTS

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 or murine norovirus (MNV) as a model for human norovirus.

Viral Immune Evasion

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Evolutionarily successful viruses must overcome the host innate and adaptive immune responses.  For unclear reasons, immunity against human norovirus is transient and inadequate.  Using the closely related murine norovirus, it has been shown that the norovirus non-structural protein NS1/2  can counteract the host interferon response. In addition, norovirus infected tuft cells are resistant to norovirus-specific CD8+ T cells. Elucidating the mechanisms of norovirus immune evasion has important implications for our understanding of human norovirus transmission and vaccine design.

Type II Immunity and Viral Infection

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Intestinal worms and parasites (such as Tritrichomonas muris, above) elicit a type II immune response characterized by production of the cytokines IL4-, IL-5, and IL-13 which facilitate clearance of the worms and parasites.  Surprisingly, this anti-worm immune response exacerbates norovirus infection.  Understanding this complex interaction has important implications for norovirus pathogenesis given the epidemiologic link between worm-endemic countries and deaths attributed to norovirus infection.

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.