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Siddle, Katherine

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Siddle

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Katherine

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Siddle, Katherine
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    Widespread Shortening of 3’ Untranslated Regions and Increased Exon Inclusion Are Evolutionarily Conserved Features of Innate Immune Responses to Infection
    (Public Library of Science, 2016) Pai, Athma A.; Baharian, Golshid; Pagé Sabourin, Ariane; Brinkworth, Jessica F.; Nédélec, Yohann; Foley, Joseph W.; Grenier, Jean-Christophe; Siddle, Katherine; Dumaine, Anne; Yotova, Vania; Johnson, Zachary P.; Lanford, Robert E.; Burge, Christopher B.; Barreiro, Luis B.
    The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, characterized by an overall increase in isoform diversity after infection. In response to both bacteria, we found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3’ UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Following infection, we identify candidate RNA processing factors whose expression is associated with individual-specific variation in isoform abundance. Finally, by profiling microRNA levels, we show that 3’ UTRs with reduced abundance after infection are significantly enriched for target sites for particular miRNAs. These results suggest that the pervasive usage of shorter 3’ UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results suggest that dynamic changes in RNA processing may play key roles in the regulation of innate immune responses.
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    Synthetic DNA spike-ins (SDSIs) enable sample tracking and detection of inter-sample contamination in SARS-CoV-2 sequencing workflows
    (Springer Science and Business Media LLC, 2021-12-14) Lagerborg, Kim A; Normandin, Erica; Bauer, Matthew; Adams, Gordon; Figueroa, Katherine; Loreth, Christine; Gladden-Young, Adrianne; Shaw, Bennett; Pearlman, Leah; Berenzy, Daniel; Dewey, Hannah; Kales, Susan; Dobbins, Sabrina; Seiguer Shenoy, Erica; Hooper, David; Pierce, Virginia; Zachary, Kimon; Park, Daniel; Macinnis, Bronwyn; Tewhey, Ryan; Lemieux, Jacob; Sabeti, Pardis; Reilly, Steven; Siddle, Katherine
    The global spread and continued evolution of SARS-CoV-2 has driven an unprecedented surge in viral genomic surveillance. Amplicon-based sequencing methods provide a sensitive, low-cost and rapid approach but suffer a high potential for contamination, which can undermine laboratory processes and results. This challenge will only increase with expanding global production of sequences by diverse laboratories for epidemiological and clinical interpretation, as well in genomic surveillance in future outbreaks. We present SDSI+AmpSeq, an approach which uses synthetic DNA spike-ins (SDSIs) to track samples and detect inter-sample contamination through the sequencing workflow. Applying SDSIs to the ARTIC Consortium’s amplicon design, we demonstrate their utility and efficiency in a real-time investigation of a suspected hospital cluster of SARS-CoV-2 cases and across thousands of diagnostic samples at multiple laboratories. We establish that SDSI+AmpSeq provides increased confidence in genomic data by detecting and in some cases correcting for relatively common, yet previously unobserved modes of error without impacting genome recovery.
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    Field validation of recombinant antigen immunoassays for diagnosis of Lassa fever
    (Nature Publishing Group UK, 2018) Boisen, Matthew L.; Hartnett, Jessica N.; Shaffer, Jeffrey G.; Goba, Augustine; Momoh, Mambu; Sandi, John Demby; Fullah, Mohamed; Nelson, Diana K. S.; Bush, Duane J.; Rowland, Megan M.; Heinrich, Megan L.; Koval, Anatoliy P.; Cross, Robert W.; Barnes, Kayle; Lachenauer, Anna E.; Lin, Aaron; Nekoui, Mahan; Kotliar, Dylan; Winnicki, Sarah; Siddle, Katherine; Gbakie, Michael; Fonnie, Mbalu; Koroma, Veronica J.; Kanneh, Lansana; Kulakosky, Peter C.; Hastie, Kathryn M.; Wilson, Russell B.; Andersen, Kristian G.; Folarin, Onikepe O.; Happi, Christian T.; Sabeti, Pardis; Geisbert, Thomas W.; Saphire, Erica Ollmann; Khan, S. Humarr; Grant, Donald S.; Schieffelin, John S.; Branco, Luis M.; Garry, Robert F.
    Lassa fever, a hemorrhagic fever caused by Lassa virus (LASV), is endemic in West Africa. It is difficult to distinguish febrile illnesses that are common in West Africa from Lassa fever based solely on a patient’s clinical presentation. The field performance of recombinant antigen-based Lassa fever immunoassays was compared to that of quantitative polymerase chain assays (qPCRs) using samples from subjects meeting the case definition of Lassa fever presenting to Kenema Government Hospital in Sierra Leone. The recombinant Lassa virus (ReLASV) enzyme-linked immunosorbant assay (ELISA) for detection of viral antigen in blood performed with 95% sensitivity and 97% specificity using a diagnostic standard that combined results of the immunoassays and qPCR. The ReLASV rapid diagnostic test (RDT), a lateral flow immunoassay based on paired monoclonal antibodies to the Josiah strain of LASV (lineage IV), performed with 90% sensitivity and 100% specificity. ReLASV immunoassays performed better than the most robust qPCR currently available, which had 82% sensitivity and 95% specificity. The performance characteristics of recombinant antigen-based Lassa virus immunoassays indicate that they can aid in the diagnosis of LASV Infection and inform the clinical management of Lassa fever patients.