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Principal Investigator: Emily R Troemel
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $386,805
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Animals><Anti-viral Response><Behavior><Binding><Blood><Blood Reticuloendothelial System><Body Tissues><C elegans><C elegans genome><C. elegans><C. elegans genome><C.elegans><C.elegans genome><COVID-19 virus><COVID19 virus><Cachectin><Caenorhabditis elegans><Caenorhabditis elegans genome><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><CoV-2><CoV2><DNA Helicases><DNA Unwinding Proteins><DNA unwinding enzyme><Data><Disease><Disorder><Double-Stranded RNA><Epithelial Cells><Epithelium><FISH Technic><FISH Technique><FISH analysis><FISH assay><Fluorescence In Situ Hybridization><Fluorescent in Situ Hybridization><France><Gene Expression><Gene Transcription><GeneHomolog><Genes><Genetic><Genetic Transcription><Genetic analyses><Genomics><Goals><Health><Homolog><Homologous Gene><Homologue><Human><IFN><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune><Immune response><Immunes><Immunoglobulin Enhancer-Binding Protein><Immunological response><Infection><Inflammatory><Innate Immune Response><Innate Immunity><Interferon Regulatory Factor 3><Interferon Type I><Interferons><Intestinal><Intestines><Intracellular Communication and Signaling><Ions><Knowledge><Macrophage-Derived TNF><Mammalia><Mammals><Measures><Methods><Microscopy><Microspora><Microsporea><Microsporida><Microsporidia><Mission><Modeling><Modern Man><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Muscle><Muscle Tissue><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIH><Names><National Institutes of Health><Native Immunity><Natural Immunity><Nematoda><Nematodes><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Organism><Outcome><Pathway interactions><Pattern><Planets><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><Proteomics><Public Health><RNA><RNA Expression><RNA Gene Products><RNA Interference><RNA Silencing><RNA Virus Infections><RNA Viruses><RNA viral infection><RNAi><Receptor Protein><Regulation><Reporter><Research><Resistance><Ribonucleic Acid><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sequence-Specific Posttranscriptional Gene Silencing><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Surface><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Tissues><Transcription><Transcription Factor NF-kB><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States National Institutes of Health><Up-Regulation><Upregulation><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Visualization><Vulnerable Populations><Work><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><anti-viral immunity><antiviral immunity><biological signal transduction><bowel><burden of disease><burden of illness><candidate identification><cell type><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytosolic receptor><disease burden><dsRNA><fighting><fungal pathogen><fungi pathogen><genetic analysis><hCoV19><helicase><host response><immune system response><immunoresponse><in vivo><innovate><innovation><innovative><insight><intestinal epithelium><kappa B Enhancer Binding Protein><living system><muscular><mutant><nCoV2><name><named><naming><neuronal><novel><nuclear factor kappa beta><overexpress><overexpression><pandemic><pandemic disease><pathogen><pathogenic fungus><pathway><receptor><resistant><response><roundworm><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><tool><transcriptomics><triphosphate><tripolyphosphate><viral detection><viral infection><viral multiplication><viral replication><virus detection><virus infection><virus multiplication><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people>