Christine M O'Connor,  PhD

Christine M O'Connor, PhD

Associate Staff

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195

 

Our lab focuses on understanding the host-pathogen relationship during human herpesvirus infection. Herpesviruses are large, double-stranded DNA viruses that establish life-long infections. After initial infection, herpesviruses establish a latent infection, resulting in the carriage of the viral genome and restricted active viral replication. While herpesviruses persist latently for the majority of the time, immune insult induces sporadic reactivation events, resulting in clinical presentation of disease that can range from mostly inapparent to severe, and in some cases, cause mortality.

Our lab’s main interest lies in understanding the betaherpesvirus, human cytomegalovirus (HCMV), a ubiquitous pathogen that infects nearly 80% of the population by 40 years of age. HCMV remains latent within progenitor cells of the host’s hematopoietic compartment, and upon reactivation, is problematic for those with weakened immune systems. A complete understanding of the cellular and viral factors that facilitate viral latency and reactivation remain outstanding, and thus, is a major focus of our lab. Current research projects in this area include:

  • HCMV-induced host cell alterations during latency and reactivation.
    • Viral-encoded GPCR regulation of latency and reactivation
      • Mechanisms underlying CMV US28-regulated signaling towards establishing and maintaining viral latency
      • CMV UL33-mediated viral reactivation
      • Coordinated functions of the CMV-encoded GPCRs during latency and reactivation
    • Regulation of the HCMV Major Immediate Early Promoter (MIEP)
      • Epigenetic modifications regulating MIEP silencing and activation
      • Transcription factor regulation of the MIEP
  • HCMV’s influence on human health
    • Contribution of HCMV to the progression of glioblastoma
    • Impact of HCMV on the aged
    • HCMV immunopathology
  • Host-pathogen interactions during HCMV lytic infection
    • Impact of HCMV on NCAPD3/condensin II-mediated chromatin organization and gene transcription
    • Influence of HCMV-encoded GPCRs on efficient viral replication

Viral infection of host cells results in a rapid defense from the host as a protective measure. However, pathogens, including herpesviruses, use countermeasures to subvert these robust host responses. This “arms race” is continual throughout infection, and understanding the repertoire of host measures and viral countermeasures is paramount to controlling infection. The O’Connor Lab aims to understand the innate immune response to herpesvirus infection, using the prototypical alphaherpesvirus, herpes simplex virus (HSV), as well as HCMV. Current projects include:

  • Innate immune response to herpesviruses
    • Innate responses to HCMV
      • HCMV-encoded GPCR regulation of innate factors during lytic and latent infection
    • Innate responses to HSV
      • TLR-mediated response to HSV infection
      • HSV-1-mediated IFN-induced protein (IFIT) induction
      • cGAS/STING activation following HSV infection

Lay Summary

Human herpesviruses are prevelant in the population, resulting in infections that remain latent, or quiet, in the host for life. However, when an individual’s immune system is weakened, these viruses can "wake up", or reactivate, to cause severe complications and often death. Dr. O’Connor’s research focuses on the host-pathogen relationship following herpesvirus infection that influence viral pathogenesis and disease progression.


Select publication (complete list of published work - https://www.ncbi.nlm.nih.gov/myncbi/1J5ZF34E-255E/bibliography/public/?sortby=pubDate&sdirection=descending):

  1. Smith NA, Chan GC*, O'Connor CM* (2021) Modulation of host cell signlaing during cytomegalovirus latency and reactivation Virology J 18(1) PMC8524946 (*co-corresponding authors)
  2. O'Connor CM* and Sen GC* (2021) Innate immune responses to herpesvirus infection. Cells 10(8): 2122. PMC8394705 (*co-corresponding authors)
  3. Krishna BA, Wass AB, Dooley AL, O'Connor CM (2021) CMV-encoded GPCR pUL33 activates CREB and facilitates its recruitment to the MIE locus for efficient viral reactivation. J Cell Sci 134:jcs.254268. PMC7860128
  4. Dooley AL and O'Connor CM (2020) Regulation of the MIE locus during HCMV latency and reactivation. Pathogens 9(11): 869. PMC7690695
  5. Krishna BA, Wass AB, O'Connor CM (2020) Activator protein-1 transactivation of the major immediate early locus is a determinant of cytomegalovirus reactivation from latency. PNAS 117(34): 20860-20867. PMC7456108
  6. Tu CC, O'Connor CM, Spencer JV (2020) Identification of a novel signaling complex containing host chemokine receptor CXCR4, IL-10 receptor, and human cytomegalovirus US27. Virology. 548:49-58. PMID: 32838946
  7. Krishna BA, Wass AB, O'Connor CM (2020) The requirement for US28 in establishing and maintaining latency is independent of US27 and US29 gene expression. Front Cell Infect Microbiol 10:186 PMC7198828
  8. Elder EG, Krishna BA, Williamson J, Lim EY, Poole E, Sedikides GX, Wills M, O'Connor CM, Lehner PJ, Sinclair J (2019) Interferon-responsive genes are targeted during the establishment of human cytomegalovirus latency. mBio 10(6): e02574-19. PMC6890990
  9. Krishna BA, Humby MS, Miller WE, and O’Connor CM. (2019) The human cytomegalovirus G-protein coupled receptor US28 promotes latency by attenuating c-fos. PNAS 116(5): 1755-1764. PMC6358704
  10. Nukui M, Murphy EA*, O’Connor CM*. (2018) The natural flavonoid compound deguelin inhibits HCMV lytic replication within fibroblasts.Viruses 10(11): pii: E614. PMC6265796 (*co-corresponding authors)
  11. Boeck JM, Stowell GA, O’Connor CM, Spencer JV. (2018) The human cytomegalovirus US27 gene product constitutively activates ARE-mediated transcription through Gβγ, PI3K, and NRF-1. J Virol. 92(23):pii: e00644-18. PMC6232467
  12. Roche KL, Nukui M, Krishna BA, O’Connor CM, Murphy EA. (2018) Selective 4-thiouracil labeling of RNA transcripts within latently infected cells after infection with human cytomegalovirus expressing functional uracil phosphoribosyltransferase. J Virol. 92(21): pii:e00880-18. PMC6189490
  13. Krishna BA, Miller WE, and O’Connor CM. (2018) US28: HCMV’s Swiss Army Knife. Viruses 10(8): pii: E445.
  14. Tu CC, Arnolds KL, O’Connor CM, Spencer JV. (2018) Human cytomegalovirus UL111A and US27 gene products enhance the CXCL12/CXCR4 signaling axis via distinct mechanisms. J. Virol. 92(5):e01981-17. PMC5809719
  15. O’Connor CM, Nukui M, Gurova K, Murphy EA. Inhibition of the Facilitates Chromatin Transcription (FACT) complex reduces transcription from the HCMV MIEP in models of lytic and latent replication. J Virol. 2016;90(8):4249-53. PMC4810550
  16. Humby MS and O’Connor CM. HCMV US28 is important for latent infection of hematopoietic progenitor cells. J Virol. 2015; 90(6): 2959-70. PMC4810657
  17. O'Connor CM, DiMaggio PA Jr, Shenk T, and Garcia BA. Quantitative proteomic discovery of dynamic epigenome changes that control human cytomegalovirus infection. Mol Cell Proteomics. 2014;13:2399-2410. PMC4159657
  18. O’Connor CM, Vanicek J, Murphy EA. Host miRNA regulation of human cytomegalovirus immediate early protein translation promotes viral latency. J Virol. 2014;88(10):5524-32. PMC4019081
  19. Miller WE, Zagorski WA, Brenneman JD, Avery D, Miller JLC, O’Connor CM. US28 is a ubiquitous and potent activator of phospholipase C during productive infection of clinically relevant HCMV target cells. PLoS One. 2012;7(11):e50524. PMC3510093


03/30/2021 |  

NIH Awards $4.6M to Study Human Cytomegalovirus Latency and Reactivation

Dr. O’Connor’s team will investigate the underlying mechanisms by which human cytomegalovirus manipulates host cells to regulate viral latency and reactivation.




03/19/2021 |  

New NIH Grant to Study Antiviral Factor in Human Cytomegalovirus

With this funding, Drs. O’Connor and Longworth will investigate how host cells attempt to subvert human cytomegalovirus replication.




10/05/2020 |  

GMI Graduate Students Win 2020 Lerner Research Institute Awards for Excellence

Sara Akhavanfard, MD, PhD, and Abigail Dooley were recognized for their outstanding scientific achievements.