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Bonita J.
Biegalke, Ph.D.
Associate Professor
Department of Biomedical Sciences
biegalke@ohiou.edu
227 Life Sciences Research Building
740-593-2377 |
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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. |
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