Date of Award
Doctor of Philosophy (PhD)
Gammaherpesviruses are oncogenic viruses that establish latent infection and can periodically reactivate. Replication, reactivation from latency and gammaherpesvirus-mediated pathology are regulated by viral and host factors. Long-standing interests in the field include understanding viral gene expression and regulation during lytic and latent infection and the effects of chronic viral infection on the host. Murine gammaherpesvirus 68 (MHV68) is used to model features of human gammaherpesvirus biology.
In this dissertation, I investigated: (1) the function of antisense viral transcripts; (2) Stat1 regulation of MHV68 gene 50 promoters; and (3) the effect of chronic infection on host gene expression. Our laboratory identified extensive transcription outside of annotated open reading frames (ORFs) in the MHV68 genome, which we termed expressed genomic regions (EGRs). Similar pervasive transcription is also observed in the related human gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV). Despite their prevalence, the functions of these novel transcripts are largely unknown. To study their function in MHV68 gene expression, we targeted thirteen EGRs using strand-specific antisense oligonucleotides and found targeting of six EGRs reduced late viral gene expression. We identified three transcripts enriched in the nucleus of infected cells, the first putative nuclear noncoding RNA to be identified in MHV68.
ORF50, the latent-to-lytic switch gene in MHV68 and KSHV, is sufficient to induce lytic reactivation from latently infected cells. We determined that interferon-gamma (IFNg), which controls viral reactivation of MHV68, suppressed ORF50 transcription by regulating its promoters in a Stat1-dependent manner, suggesting that the virus maintains Stat1-responsive elements to control the viral life cycle.
To assess the effect of chronic viral infection on host gene expression, we analyzed the transcriptional profile of tissues from latently infected mice and identified over 600 differentially expressed genes. We identified organ-specific transcriptional changes in gene expression. Most differentially expressed genes were involved in immune signaling, immune response, or cell cycle pathways and many were associated with IFNg signaling.
Taken together, these studies provide the first functional evidence for the importance of regions of pervasive transcription in MHV68 and add to our understanding of how the cytokine, IFNg, controls viral infection and may modulate gene transcription in the host.
Chair and Committee
Herbert W Virgin
Michael Diamond, Deborah Lenschow, Eugene Oltz, Jean Schaffer, Wayne Yokoyama
Canny, Susan Priscilla, "Regulation of Host and Viral RNA Expression during Gammaherpesvirus Infection" (2015). Arts & Sciences Electronic Theses and Dissertations. 462.