Christina O'Grady, PhD

Tina O’Grady’s research integrates analysis of genomic, transcriptomic and proteomic datasets with wet lab results to answer medically relevant questions about viral infection, immunology and cancer.

Nonsense-mediated RNA Decay (NMD) is a highly conserved cellular quality control pathway that degrades many mutant or aberrantly spliced RNA transcripts. Reports in the literature have recently linked NMD processes to oncogenesis and metastasis, in complex and sometimes contradictory ways. Often considered a tumor suppressor pathway, NMD is frequently downregulated in cancers, resulting in higher expression of (sometimes mutated) oncogenes. On the other hand, some cancers appear to harness or even enhance the NMD system to degrade transcripts of tumor suppressor genes, dysregulating oncogene expression and leading to increased cancer cell proliferation.

EBV is a ubiquitous human pathogen that infects more than90% of the world’s population and is

associated with cancers including lymphomas, gastriccarcinoma and nasopharyngeal carcinoma.

Typically, EBV persists in host B cells in a latent phase, during which time limited viral gene expression shields the virus from the host immune system. Periodically, reactivation of the lytic cycle leads to viral takeover of the host cell and production of new infectious virions, facilitating viral spread. Interestingly, some EBV RNA transcripts expressed during reactivation appear to be NMD targets. Our studies have revealed that EBV actively inhibits host cellular NMD during lytic reactivation, presumably preventing degradation of viral RNA transcripts and facilitating viral protein translation and virion production. In contrast, we find that the NMD pathway is active during the latency phase where it likely promotes cell proliferation while simultaneously preventing viral lytic reactivation. These two opposite modes of engagement form a sort of “yin and yang” relationship between EBV and host NMD, playing a key role in governing the virus’s biphasic infection strategy.

We are investigating this novel dynamic viral interface with a host system to determine the mechanistic underpinnings of EBV-NMD interactions and determine the functional impact on viral

reactivation, viral latency and lymphoma cell growth and proliferation.

SelectedPublications:

1. O’Grady TM,     Baddoo M, Flemington SA, Ishaq EY, Ungerleider NA and Flemington EK*.     2022. Reversal of splicing infidelity is an early step in preparation of     naïve B cells for activation. Frontiers in Immunology 13:1060114.
2. O’Grady     T, Njock MS, Lion M, Bruyr J, Mariavelle E, Galvan B, Boeckx A, Struman I     and Dequiedt F. 2022. Sorting and packaging of RNA into extracellular     vesicles shape intracellular transcript levels. BMC Biology 20:72.
3. O’Grady T, Feswick A, Hoffman B,     Wang Y, Medina EM, Kara M, van Dyck LF, Flemington EK and Tibbetts S.     2019. Genome-wide transcript structure resolution reveals abundant     alternate isoform usage from murine gammaherpesvirus 68. Cell Reports 27:3988-4002.

 ORCID:0000-0002-1283-0293

https://www.ncbi.nlm.nih.gov/sites/myncbi/1ZY9lx29UaYkm/bibliography/40040907/public/

Topics/keywords: Epstein BarrVirus, EBV, Lymphoma, RNA, B cells

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