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Gehrke, Lee

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Gehrke

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Lee

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Gehrke, Lee

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2014 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.5be239f5-70c0-4846-bd8c-7a83b7e43e95

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    Field-deployable viral diagnostics using CRISPR-Cas13
    Yozwiak, Nathan; Michael, Scott; Isern, Sharon; Nogueira, Mauricio; Barnes, Kayle; Freije, Catherine; Sabeti, Pardis; Abudayyeh, Omar; Gehrke, Lee; Myhrvold, Cameron; Bosch, Irene; Durbin, Ann; Gootenberg, Jonathan; Kellner, Max; Zhang, Feng; Metsky, Hayden; Tan, Amanda; Parham, Leda; Garcia, Kimberly; Lorenzana, Ivette; Chak, Bridget; Mondini, Adriano; Macinnis, Bronwyn; Paul, Lauren
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    Diverse intracellular pathogens activate Type III Interferon expression from peroxisomes
    (2014) Odendall, Charlotte; Dixit, Evelyn; Stavru, Fabrizia; Bierne, Helene; Franz, Kate M.; Fiegen, Ann; Boulant, Steeve; Gehrke, Lee; Cossart, Pascale; Kagan, Jonathan
    Type I Interferon (IFN) responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of Type I IFNs. The mechanisms controlling Type I IFN-independent responses are undefined. We have found that RIG-I like Receptors (RLRs) induce Type III IFN expression in a variety of human cell types, and identified factors that differentially regulate Type I and III IFN expression. We identified peroxisomes as a primary site that initiates Type III IFN expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust Type III IFN responses in human cells. These findings highlight the interconnections between innate immunity and cell biology.
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    RNAs Containing Modified Nucleotides Fail To Trigger RIG-I Conformational Changes for Innate Immune Signaling
    (American Society for Microbiology, 2016) Fiegen, Ann; Wang, Chen; Marcotrigiano, Joseph; Gehrke, Lee
    ABSTRACT Invading pathogen nucleic acids are recognized and bound by cytoplasmic (retinoic acid-inducible gene I [RIG-I]-like) and membrane-bound (Toll-like) pattern recognition receptors to activate innate immune signaling. Modified nucleotides, when present in RNA molecules, diminish the magnitude of these signaling responses. However, mechanisms explaining the blunted signaling have not been elucidated. In this study, we used several independent biological assays, including inhibition of virus replication, RIG-I:RNA binding assays, and limited trypsin digestion of RIG-I:RNA complexes, to begin to understand how RNAs containing modified nucleotides avoid or suppress innate immune signaling. The experiments were based on a model innate immune activating RNA molecule, the polyU/UC RNA domain of hepatitis C virus, which was transcribed in vitro with canonical nucleotides or with one of eight modified nucleotides. The approach revealed signature assay responses associated with individual modified nucleotides or classes of modified nucleotides. For example, while both N-6-methyladenosine (m6A) and pseudouridine nucleotides correlate with diminished signaling, RNA containing m6A modifications bound RIG-I poorly, while RNA containing pseudouridine bound RIG-I with high affinity but failed to trigger the canonical RIG-I conformational changes associated with robust signaling. These data advance understanding of RNA-mediated innate immune signaling, with additional relevance for applying nucleotide modifications to RNA therapeutics.
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    Zika virus evolution and spread in the Americas
    (SpringerNature, 2017) Metsky, Hayden C; Matranga, Christian B; Wohl, Shirlee; Schaffner, Stephen; Freije, Catherine; Winnicki, Sarah; West, Kendra L.; Qu, James; Baniecki, Mary; Gladden-Young, Adrianne; Lin, Aaron; Tomkins-Tinch, Christopher; Ye, Simon H; Park, Daniel; Luo, Cynthia; Barnes, Kayle; Shah, Rickey; Chak, Bridget; Barbosa-Lima, Giselle; Delatorre, Edson; Vieira, Yasmine R; Paul, Lauren M; Tan, Amanda L; Barcellona, Carolyn M; Porcelli, Mario C; Vasquez, Chalmers; Cannons, Andrew C; Cone, Marshall R; Hogan, Kelly N; Kopp, Edgar W; Anzinger, Joshua J; Garcia, Kimberly F; Parham, Leda A; Gelvez Ramirez, Rosa Margarita; Miranda Montoya, Maria Consuelo; Rojas, Diana P; Brown, Catherine M; Hennigan, Scott; Sabina, Brandon; Scotland, Sarah; Gangavarapu, Karthik; Grubaugh, Nathan D; Oliveira, Glenn; Robles-Sikisaka, Refugio; Rambaut, Andrew; Gehrke, Lee; Smole, Sandra; Halloran, M Elizabeth; Villar Centeno, Luis Angel; Mattar, Salim; Lorenzana, Ivette; Cerbino-Neto, Jose; Valim, Clarissa; Degrave, Wim; Bozza, Patricia T; Gnirke, Andreas; Andersen, Kristian G; Isern, Sharon; Michael, Scott; Bozza, Fernando A; Souza, Thiago ML; Bosch, Irene; Yozwiak, Nathan L; MacInnis, Bronwyn L; Sabeti, Pardis
    Despite great attention given to the recent Zika virus (ZIKV) epidemic in the Americas, much remains unknown about its epidemiology and evolution, in part due to a lack of genomic data. We applied multiple sequencing approaches to generate 100 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analyzed the timing and patterns of introductions into distinct geographic regions, confirming phylogenetic evidence for the origin and rapid expansion of the outbreak in Brazil, and for multiple introductions from Brazil into Honduras, Colombia, Puerto Rico, other Caribbean islands, and the continental US. We find that ZIKV circulated undetected in many regions of the Americas for up to a year before the first locally transmitted cases were confirmed, highlighting the challenge of effective surveillance for this virus. We further characterize genetic variation across the outbreak to identify mutations with possible functional implications for ZIKV biology and pathogenesis.