Location: Cleveland Clinic Main Campus
Human cytomegalovirus (HCMV) is a herpesvirus that is prevalent in the population, where it remains latent, or quiet, in the host for life. However, when an individual’s immune system is weakened, the virus can wake up, or reactivate, to cause severe complications and often death. Dr. O’Connor’s research focuses on the processes that allow the virus to re-awaken after long periods of dormancy, and how this event leads to viral pathogenesis and disease progression.
The betaherpesvirus human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects nearly 80% of the population by 40 years of age. Like all herpesviruses, HCMV infections are life-long, where the virus remains latent within progenitor cells of the host’s hematopoietic compartment. Healthy individuals, for the most part, remain asymptomatic. However, infection is problematic for those with weakened immune systems, where reactivation of HCMV from latency can cause severe morbidity and mortality. In addition to immunocomprimised patients, HCMV reactivation poses an additional threat to those with atherosclerosis and certain cancers (e.g., glioblastoma). In fact, viral DNA is found in the arterial walls of atherosclerosis patients and in a vast majority of glioblastoma tumors tested to-date. HCMV has the capacity to encode over 200 open reading frames (ORFs), four of which are G-protein-coupled receptor (GPCR) homologs: UL33, UL78, US27, and US28. Cellular GPCRs are signaling proteins that, when activated, can induce a variety of downstream signaling events, thereby altering the host cell environment. Although these viral GPCRs are homologous to cellular GPCRs by sequence analysis, only UL33 and US28 have known signaling properties. The four HCMV-encoded GPCRs are expressed during the lytic life cycle of the virus, yet the impact these four proteins have on this phase of the viral life cycle is incomplete. During latency, only a handful of HCMV genes are expressed, including US28. We hypothesize that US28 influences HCMV latency via specific signaling pathways during this phase of infection.
Research in the O’Connor lab aims to elucidate the functions of the HCMV-encoded GPCRs during both lytic and latent infection to better understand how these proteins influence pathogenesis and subsequent disease. The lab currently focuses on three main areas of research:
Taken together, research in the O’Connor lab is aimed at gaining a better understanding of how the HCMV GPCRs mediate viral infection, as well as the host cell milieu, toward accelerating disease processes. More than two-thirds of approved drugs target the GPCR family of proteins, making the HCMV GPCRs ideal therapeutic targets. Defining a role for these viral proteins in pathogenesis will provide avenues for novel therapeutics that may aid in preventing and/or slowing the progress of HCMV-associated disease.
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The findings identify potential drug targets for a virus that has no vaccine or cure.
Dr. O’Connor’s team will investigate the underlying mechanisms by which human cytomegalovirus manipulates host cells to regulate viral latency and reactivation.
With this funding, Drs. O’Connor and Longworth will investigate how host cells attempt to subvert human cytomegalovirus replication.
Sara Akhavanfard, MD, PhD, and Abigail Dooley were recognized for their outstanding scientific achievements.