Bonita J. Biegalke, Ph.D.
Associate Chair, Department of Biomedical Sciences
Associate Professor of Virology
biegalke@ohio.edu
227 Life Sciences Research Building
740-593-2377
FACULTY MEMBER QUICK LINKS
FACULTY MEMBER HOME
RESEARCH
BIOGRAPHICAL SKETCH
PUBLICATIONS
TEACHING
CYTOMEGALOVIRUS
USEFUL LINKS
CURRICULUM VITAE

DEPT. OF BIOMEDICAL SCIENCES
DEPT. OF BIOLOGICAL SCIENCES
MOLECULAR & CELLULAR BIOLOGY PROGRAM
EDISON BIOTECHNOLOGY INSTITUTE
COLLEGE OF OSTEOPATHIC MEDICINE
 
 
Viruses have been the subject of intensive scientific scrutiny for two major reasons: 1) viral infections are associated with disease in animals and plants and 2) viruses have served as excellent tools to probe the inner workings of cells. My research focuses on using cytomegalovirus (CMV) as a tool to understand general mechanisms of gene regulation and simultaneously, to better understand the mechanisms that control CMV replication and lead to development of disease.

Human cytomegalovirus (HCMV) is a member of the herpes viruses and shares a number of features with the other herpes viruses including a large double-strand DNA genome and the ability to establish latent infections. HCMV is predominantly an opportunistic pathogen and causes a wide variety of disease syndromes in immuno-incompetent individuals including neonates, transplant recipients and people with AIDS. Some of the disease syndromes that are seen include mental retardation and deafness in infants, pneumonitis in bone marrow transplant recipients, and retinitis in AIDS patients.

Replication of the virus commences with the expression of one category of viral genes, the immediate early genes. The immediate early genes encode proteins that are regulatory in nature and control expression of viral and cellular genes. Synthesis of immediate early proteins results in the expression of early genes and then later in infection, in the expression of late genes. Early genes encode proteins involved in replication of the viral genome; late genes encode proteins involved in virion assembly, maturation and egress.

Expression of immediate early proteins is postulated to provide a determination point for viral infection, determining whether the virus becomes latent or goes on to replicate with associated cytopathology. I am interested in the regulation of immediate early gene expression and the roles of immediate early proteins in viral replication, pathogenicity and establishment of latent infections.

Research in the lab has been focused on one of the immediate early genes, the US3 gene. The US3 gene encodes three alternatively spliced transcripts which are synthesizzed at immediate early times after infection. The US3 proteins have regulatory functions and regulate transcription of the cellular gene, hsp70, synergistically with proteins encoded by another immediate early gene complex, UL36-38. In addition, US3 proteins cause the major histocompatibility heavy chain class I protein to be retained in the endoplasmic reticulum. Thus, the US3 gene product blocks antigen-presentation by the infected host cell early after viral infection. The contribution of US3 proteins to viral evasion of the immune system is believed to be important for the establishment of viral infection in the human host. Furthermore, the functions of the US3 proteins suggest that the US3 gene plays an important role in pathogenicity of the virus.

Expression of the US3 gene is subject to complex regulation with transcription controlled by silencer, enhancer, and transcriptional repressor elements. The silencer and enhancer elements regulate US3 transcription in a cell type-specific manner. In addition to the silencer and enhancer elements, I have demonstrated that US3 transcription is also regulated by sequences located between the TATA box and the transcription start site. These sequences, termed the transcriptional repressor element (tre), act to repress transcription from the US3 promoter, following viral infection and protein synthesis. My laboratory has identified the protein that binds to the tre as the product of the viral UL34 gene. The UL34 protein (pUL34) binds to the tre and mediates transcriptional repression. There are a number of potential pUL34 binding sites throughout the HCMV genome, suggesting that UL34 will play additional roles in regulating viral gene expression and viral replication.

We are also investigating the role of the US3 proteins during viral infection. We have shown that only one of the three proteins synthesized by the US3 gene binds to and retains major histocompatibility antigens in the endoplasmic reticulum. The other two US3 proteins localize to the secretory pathway and to the Golgi apparatus, suggesting that they will have additional functions during replication of the virus in the infected host.

An additional area of investigation that I am interested in is a gene flanking UL34. We have shown that the UL35 gene encodes two distinct, yet related proteins. The two UL35 proteins differentially localize during infection, with the larger of the two proteins becoming part of newly assembled viral particles. Further studies will analyze the UL35 proteins for functional domains.

The work ongoing in my laboratory is identifying regulatory mechanisms used by HCMV; mechanisms that are predicted to be used to regulate normal cellular gene expression. Thus, by using a virus, I can extend our understanding of cellular mechanisms while gaining an understanding of HCMV. These studies will expand our understanding of the virus,leading to improved therapeutic and preventive treatment regimens for HCMV infection.
   
   
  Ohio University
Heritage College of Osteopathic Medicine
Irvine Hall, Athens, Ohio 45701
740-593-2530 740-597-2778 fax
 
Last updated: 04/03/2014