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Christine O'Connor, PhD

Christine O'Connor, PhD
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Department LRI Infection Biology
Primary Location Cleveland Clinic Main Campus
Type of Doctor Adults Only
Languages English
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Biography

About Christine O'Connor, PhD

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. Our work 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.

We currently focus on three main areas of research:

1. Defining the contribution of the HCMV GPCRs to lytic replication

We have shown that the HCMV GPCRs have a variety of functions during HCMV infection. We have demonstrated the importance of US27 in extracellular spread of the virus. In parallel, we found that US27 is dispensable for viral growth in epithelial cells, where the mode of viral spread is restricted to cell-to-cell. In contrast, we have shown that UL78 is required for efficient viral infection in epithelial cells, as it functions during entry. We are currently investigating the additive contribution of these proteins towards promoting a successful lytic infection.

2. Understanding the role of US28 during HCMV latency

US28 is expressed during both the lytic and latent cycles of HCMV infection. To elucidate its function during latent infection, we utilized a panel of mutant viruses and our novel in vitro latency model system. We have shown that HCMV US28 is required for viral latency in hematopoietic progenitor cells, as viruses that lack the US28 ORF fail to undergo latent infection and instead favor lytic replication. Further, we have shown that US28’s continued expression is necessary to maintain latency. Our current work is aimed at understanding the underlying mechanisms by which US28 influences the latent state of HCMV.

3. Elucidating the contribution of US28 towards the progression of atheroscleros.

Many US28-induced signaling cascades and the cellular factors that are subsequently altered are also involved arterial plaque formation during the progression to atherosclerosis, leading us to hypothesize that HCMV’s involvement in atherosclerotic progression could be due, at least in part, to US28-mediated events. We, and others, have described signaling properties of US28, which unlike cellular GPCRs, signals through a variety of ligands and couples to many G-proteins. US28, like some cellular GPCRs that are dysregulated during disease, can also induce signaling events in the absence of a ligand (constitutive activation). We have found that the signaling properties of US28 vary by cell type, which may lead to our understanding how HCMV accelerates disease states in various tissues. Lytically replicating HCMV, and more specifically US28, influences almost every stage of atherosclerosis, including the recruitment of immune cells to sites of injury at the vascular wall, aiding in the formation of plaques, and accelerating the mobilization of plaques to cause subsequent thrombosis and stroke. However, the mechanism(s) underlying HCMV’s contribution to these processes remain poorly understood. Our goal is to define the involvement of US28 in the acceleration of atherosclerotic disease progression by: (A) defining the host and viral factors with which US28, and the other viral GPCRs, interact to facilitate cellular processes associated with atherosclerotic progression, and (B) defining the cellular signaling pathways US28 influences during plaque formation.

Taken together, our work is aimed at gaining a better understanding of how the HCMV GPCRs mediate viral infection as well as the host cell milieu towards accelerating disease processes. Over 2/3rds 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.

In other words ...

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. Our lab 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.

Education & Professional Highlights

Education & Professional Highlights

Appointed
2010

Education & Fellowships

Fellowship - Princeton University
Princeton, NJ
2010

Medical Education - University of Virginia
Charlottesville, VA
2006

Undergraduate - Bucknell University
Lewisburg, PA
2000

Research & Publications

Research & Publications

See publications for Christine O'Connor, PhD.

(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

Industry Relationships

Industry Relationships

Cleveland Clinic physicians and scientists may collaborate with the pharmaceutical or medical device industries to help develop medical breakthroughs or provide medical expertise or education. Cleveland Clinic strives to make scientific advances that will benefit patient care and support outside relationships that promise public benefit. In order for the discoveries of Cleveland Clinic physicians' and scientists' laboratories and investigations to benefit the public, these discoveries must be commercialized in partnership with industry. As experts in their fields, Cleveland Clinic physicians and scientists are often sought after by industry to consult, provide expertise and education.

To assure professional and commercial integrity in such matters, Cleveland Clinic maintains a program that reviews these collaborations and, when appropriate, puts measures in place to minimize bias that may result from ties to industry. Cleveland Clinic publicly discloses the names of companies when (i) its physicians/scientists receive $5,000 or more per year (or, in rare cases, equity or stock options) for speaking and consulting, (ii) its physicians/scientists serve as a fiduciary, (iii) its physicians/scientists receive or have the right to receive royalties or (iv) its physicians/ scientists hold any equity interest for the physician's/scientist's role as inventor, discoverer, developer, founder or consultant.* In publicly disclosing this information, Cleveland Clinic tries to provide information as accurately as possible about its physicians' and scientists' connections with industry.

As of 6/26/2024, Dr. O'Connor has reported the financial relationships with the companies listed below. In general, patients should feel free to contact their doctor about any of the relationships and how the relationships are overseen by Cleveland Clinic. To learn more about Cleveland Clinic's policies on collaborations with industry and innovation management, go to our Integrity in Innovation page.

Public Health Service-Reportable Financial Conflicts of Interest. Cleveland Clinic scientists and physicians engage in basic, translational and clinical research activities, working to solve health problems, enhance patient care and improve quality of life for patients. Interactions with industry are essential to bringing the researchers' discoveries to the public, but can present the potential for conflicts of interest related to their research activities. Click here to view a listing of instances where Cleveland Clinic has identified a Public Health Service (PHS)-Reportable Financial Conflict of Interest and has put measures in place to ensure that, to the extent possible, the design, conduct and reporting of the research is free from bias.

* Cleveland Clinic physicians and scientists subscribe to the guidance presented in the PhRMA Code on Interactions with Healthcare Professionals and the AdvaMed Code of Ethics on Interactions with Health Care Professionals. As such, gifts of substantial value are generally prohibited.

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