Innate immunity against viral infection in intestinal epithelial cells of C. elegans

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Project Summary/Abstract RNA viruses have had an immense impact on human health. SARS-CoV-2 is only the most recent of many RNA viral zoonoses, and, even disregarding pandemics, the health burden of endemic RNA viruses, particularly in vulnerable populations, is substantial. Epithelial cells, abundant and exposed at mucosal surfaces, are often the first to be infected by RNA viruses, and are therefore often the first cell type to detect and respond to viral infection. However, unlike circulating immune cells, their in vivo behaviors cannot be measured from blood draws, and their behavior ex vivo may poorly correlate with in vivo dynamics. Our long-term goal is to understand how epithelial cells coordinate anti-viral responses in a whole-animal setting. Our previous work demonstrated that the RIG-I-like receptor (RLR) DRH-1 in the nematode C. elegans activates an anti-viral transcriptional response in intestinal epithelial cells that we named the Intracellular Pathogen Response (IPR), which protects against infections by viruses and other intracellular pathogens. We found that DRH-1 responds to infection with Orsay virus–a single-stranded, positive-sense RNA virus that naturally infects C. elegans intestinal epithelial cells. The objective of this proposal is to determine where and how DRH-1 triggers resistance to Orsay virus infection, and investigate whether in C. elegans, which lacks identified homologs of interferons, there is a role for bystander cells in mounting an immune response. The central hypothesis is that upon Orsay virus infection, DRH-1 in intestinal epithelial cells detects viral replication and induces the IPR, signaling to neighboring cells through an as-yet undescribed pathway. The rationale is based on our genetic analysis of DRH-1 and its role in anti-viral responses, and our visualization of IPR gene expression and DRH-1 localization dynamics in the context of infection. Our work is innovative because we are pursuing the IPR, which shares similarity with the type-I interferon (IFN-I) response in humans, but excitingly, appears to signal through novel factors, as homologs of MAVS, IRF3, NFkB, TNF-alpha and IFN-I itself are absent from the C. elegans genome. We will test our hypothesis with three specific aims: Aim 1) Where and how does DRH-1/RLR promote anti-viral defense in C. elegans? Aim 2) What signaling pathway is activated downstream of DRH-1/RLR in C. elegans? Aim 3) Which host cells mount an anti-viral immune response in C. elegans? The expected outcomes are to establish the signaling cascade used by DRH-1/RLR to trigger the protective IPR immune response in intestinal epithelial cells of C. elegans, and to identify the components of a systemic defense system. The proposed research is significant, because it could lead to new treatments for infections by RNA viruses, as well as a better understanding of epithelial immune defense and inflammatory diseases.