Brenda L. Fredericksen
Ph.D. - University of Tennessee Health
Science Center, 1997
Telephone: (301) 405-1251
Fax: (301) 314-9489
the molecular mechanism(s) by which flaviviruses evade and/or block
the host innate antiviral response, Molecular and cellular
mechanisms of pathogenesis of
Flaviviruses have been associated with human disease
for over a century. To date, 40 of the 73 identified species of the
Flavivirus genus have been shown to be associated with
significant human morbidity and mortality world-wide. Pathogenic
flaviviruses include yellow fever virus, dengue virus, Japanese
encephalitis virus, St. Louis virus, tick-borne encephalitis virus,
and more recently, West Nile virus (WNV). In areas of the Middle
East, Asia and Africa, where WNV has been endemic for many years,
infections are typically asymptomatic or associated with a mild
febrile illness in children.
In sharp contrast to this, recent
outbreaks in Europe, Israel and the United States have been
associated with a marked increase in both the number of reported
cases and the severity of disease among mammals and birds,
suggesting that a more pathogenic strain has emerged.
The molecular mechanisms for
the increased pathogenesis of WNV are unknown but are likely to
include novel virus-host interactions that allow WNV to overcome or
evade the host innate and/or adaptive immune response.
My laboratory is interested in
defining the molecular mechanism(s) by which flaviviruses evade
and/or block the host innate antiviral response and to clarify how
this regulation contributes to viral pathogenesis and disease. The
ability of viruses to control and/or evade the host antiviral
response is critical to the establishment of a productive infection.
As eukaryotic anti-viral programs evolved to combat invading
pathogens, viruses evolved processes to escape the anti-viral
effects of these programs. The molecular mechanisms by which WNV
overcomes the host cell anti-viral response are beginning to be
elucidated. Using microarray analysis we have recently
demonstrated that the induction of ISGs in response to infection
with WNV-NY is attenuated, which suggested that WNV-NY modulates the
host antiviral response. One of the strategies WNV uses to
circumvent the host response is to delay the activation the
transcription factor interferon regulatory factor 3 (IRF-3), which
is critical for the initiation of the antiviral response. The
delayed activation of IRF-3 allows WNV-NY to replicate virtually
unchallenged by the host cell at early times post-infection and is
essential for maximal virus production. We further demonstrated
that unlike many other viruses, which impose a nonspecific block to
the IRF-3 pathway, WNV-NY simply eludes detection by the host cell
at early in infection. To better understand this process, we
assessed the role of the pathogen recognition receptor (PRR), RIG-I,
in sensing WNV-NY infection. RIG-I null mouse embryo fibroblasts (MEFs)
retained the ability to respond to WNV-NY infection; however, the
onset of the host response was delayed compared to WT MEFs. This
suggests that RIG-I is involved in initially sensing WNV-NY
infection while other PRRs sustain and/or amplify the host response
later in infection. The delayed initiation of the host response
correlated with an increase in WNV-NY replication in RIG-I null MEFs
compared to WT MEFs. Our data suggest that activation of the host
response by RIG-I early in infection is important for controlling
replication of WNV-NY. Furthermore, pathogenic strains of WNV may
have evolved to circumvent stimulation of the host response until
after replication is well underway.
1. Fredericksen B.
L. and Gale, M. Jr. (2006). West Nile
Virus evades activation of interferon regulatory factor 3 through
RIG-I-dependent and -independent pathways without antagonizing host
defense signaling. Journal of Virology 80:2913-2923
2. Keller B.
C., Fredericksen B. L., Samuel M. A., Mock R. E., Mason P.
W., Diamond M. S., and Gale, M. J. Jr. (2006). Resistance to
alpha/beta interferon is a determinant of West Nile virus
replication fitness and virulence. Journal of Virology.
B.L., Shi, P.Y., Smit, M. , Katze, M.G.
and Gale, M. Jr. (2004). The host cell response to West Nile virus
infection limits viral spread through the activation of the
interferon regulatory 3 pathway. Journal of Virology 78:7737-7747
4. Pflugheber, J.,
Fredericksen, B. L., Sumpter R. Jr., Wang, C., Ware, L., Sodora,
D., and Gale, M.J., Jr. (2002). Regulation of PKR and IRF-1 during
hepatitis C virus RNA replication. PNAS 99:4650-4655.
B. L., Akkaraju, G., Foy, E. Wang, C., Pflugheber, J., Chen, Z.J.,
and Gale, M.J. Jr. (2002). Regulation of the interferon-beta
promoter during hepatitis C virus RNA replication.
Fredericksen B. L.,
Wei B. L, Yao J, Luo T, and Garcia J. V. (2002).
endosomal/lysosomal degradation increases the infectivity of human
immunodeficiency virus. Journal of Virology 76:11440-11446
Graduate Research Assistantships:
Projects in the
lab focus on the comparison of
the innate antiviral response to pathogenic and
nonpathogenic strains of flaviviruses in order to define the
molecular mechanisms of virulence.
My lab has 2-3 openings for
graduate student research assistants and will provide outstanding
individual research projects for them.
contact me for possible lab rotations.