BME Seminar: “Investigating the role of IFNl2/3 in controlling epithelial homeostasis in the human GI tract”

Details

Megan L. Stanifer, Ph.D.
Assistant Professor, Molecular Genetics & Microbiology
University of Florida

Abstract: Type-III interferons (or IFNλs) play important roles in antiviral defense and intestinal epithelial barrier integrity. While interferon expression has been primarily studied in response to pathogens, basal interferon expression also occurs in pathogen-free environments. However, the mechanisms regulating basal IFN-λ expression and their functions have not yet been elucidated. Here, we show that basal IFN-λ2/3 expression is linked to the development of an intact cellular epithelium characterized by formation of tight junctions and establishment of barrier function. Our findings indicate that basal IFN-λ2/3 expression depends on cGAS-STING-mediated mitochondrial DNA detection, while it is inhibited by the Hippo mechanotransduction pathway at low cellular densities. Cells lacking basal IFN-λ2/3 expression fail to develop proper tight junctions and establish normal barrier function. Mechanistically, IFN-λ2/3 suppresses Claudin-2 expression, thereby promoting barrier formation as cells become confluent. These results demonstrate a previously unknown function of basal IFNλ expression in regulating epithelial cell junction formation and highlight their importance not only during pathogen challenges but also in maintaining epithelial cell function under steady-state conditions.

Bio: Fun Fact: I love to travel, cook, and spend time with my two crazy kids. In the lab, I study how viruses try to evade sensing by the host and the mechanisms that the host uses to stop virus infection. I have used a diverse range of BSL-2 and BSL-3 viruses and have developed microscopy methods to visualize virus entry, and fusion, used single cell sequencing to unravel cell type specific responses to virus infection and implemented human mini-gut organoids to use models which more closely represent the natural infection. Our lab continues to use these techniques and focuses on virus infection at mucosal surfaces. Our primary aims are to establish complex in vitro organoid models from multiple mucosal surfaces using primary human cells to mimic the host cellular environment, to use live-cell microscopy to track virus infection and spreading within complex tissues, and to exploit fluorescent cellular reporters to follow how host cells upregulate their antiviral pathways to combat pathogen infection.