Brenda L. Fredericksen

Assistant Professor

Research Interests: Viral-host interactions, Defining the molecular mechanism(s) by which flaviviruses evade and/or block the host innate antiviral response, Molecular and cellular mechanisms of pathogenesis of flaviviruses.

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.

Selected Publications:

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. 80:9424-34.)

3. Fredericksen, 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.

5. Fredericksen, 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.  Viral Immunology. 15:29-40.

6. Fredericksen B. L., Wei B. L, Yao J, Luo T, and Garcia J. V. (2002). Inhibition of 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.  Please contact me for possible lab rotations.