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Sonja M. Best, Ph.D.
Rocky Mountain Laboratories
Building 28, Room 2A128
903 South 4th Street
Hamilton, MT 59840-2932
Phone:406-375-9694
Fax:406-375-9620​
sbest@niaid.nih.gov

Laboratory of Virology

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Sonja M. Best, Ph.D.

Photo of Sonja M Best, Ph.D.

Chief, Innate Immunity and Pathogenesis Unit, LV

Major Areas of Research

  • Mechanisms utilized by pathogenic viruses to modulate host innate immunity
  • The role of novel IFN-stimulated genes (ISGs) in host resistance to virus infection
  • The importance of dendritic cell (DC) function to anti-viral innate and adaptive immune responses
 

Program Description

The innate immune response is rapidly engaged after virus infection and functions to limit virus replication and mobilize adaptive immune responses. Viruses have evolved diverse strategies to suppress this critical host response and facilitate virus dissemination. In part, virus pathogenesis is a function of both the quality of the innate response evoked and the evasion strategies encoded by the invading pathogen. Thus, understanding the mechanisms underpinning immune activation and virus evasion will lead to improved vaccine design and novel therapeutics for treatment of both infectious and inflammatory disease.

Human dendritic cells infected with LGTV and treated with type I IFN
Human dendritic cells infected with LGTV and treated with type I IFN. The IFN-stimulated phosphorylation and nuclear localization of STAT1 (green) is inhibited in cells infected with LGTV (red).

Our current research program is shaped by the NIAID programmatic objectives in biodefense and emerging infectious disease research, namely basic research of pathogen biology and host response to develop effective vaccines and immunotherapeutics. We use flaviviruses (particularly members of the tick-borne encephalitis virus [TBEV] complex and West Nile virus [WNV]) as the primary model of infection to uncover novel cellular proteins requisite for antiviral innate immune responses and to identify virus-encoded mechanisms that antagonize these responses. These studies involve research of viruses at BSL2, BSL3 and BSL4. Our three main areas of research are outlined below.

  1. Mechanisms utilized by pathogenic viruses to modulate host innate immunity. Type I interferon (IFN) is essential to protection from flavivirus infection and has been used clinically as a potential therapeutic, albeit with limit success. This may be due to the observation that all flaviviruses examined to date antagonize IFN-dependent responses by suppressing JAK-STAT signal transduction. We originally identified NS5 as the major IFN antagonist encoded by flaviviruses, initially using Langat virus (LGTV; a member of the TBEV complex of flaviviruses) and later using WNV. Although other nonstructural proteins contribute to suppression of JAK-STAT signaling, studies by our laboratory and others suggest that NS5 is the most potent of the IFN antagonist proteins encoded by all vector-borne flaviviruses examined thus far. Hence, determining the mechanism(s) by which NS5 impedes signaling is essential to understand flavivirus pathogenesis and may lead to new therapeutic targets.
  2. The role of novel IFN-stimulated genes (ISGs) in host resistance to virus infection. It is important to understand the mechanisms underlying the anti-viral effects of IFN by identifying the function of ISGs with anti-viral activity. In particular, we are examining the role of tripartite motif (TRIM) proteins in host resistance to flavivirus replication. Many TRIM proteins are ISGs that mediate species-specific virus restriction or regulate host innate immunity. TRIM protein function is often dependent on their E3 Ubiquitin ligase activity. Therefore, we are also examining the role of ubiquitin in flavivirus replication and immune evasion.
  3. The importance of dendritic cell (DC) function to anti-viral innate and adaptive immune responses. It is essential to translate our findings to immunologically relevant cell types and animal models to understand the roles that induction and evasion of innate immunity has in development of adaptive immunity and in virus pathogenesis. We are using primary DCs and animal models to examine the importance of DCs as initial targets of infection, the role of DC pathogen recognition receptors in the immune response to infection, and how the mechanisms utilized by flaviviruses to modulate DC function affect adaptive immunity and virus pathogenesis.

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Biography

Dr. Best received her Ph.D. in biochemistry and molecular biology from the Australian National University where she studied the pathogenesis of myxoma virus, a poxvirus. She conducted her postdoctoral research at Rocky Mountain Laboratories (RML) on the complex role of apoptosis in the replication of parvoviruses. She stayed at RML as a Research Fellow and then a Staff Scientist to investigate virus-host interactions involved in flavivirus pathogenesis. It was during this time that she developed her interests in innate immunity and the molecular mechanisms utilized by flaviviruses to evade these critical host responses. In 2009, Dr. Best established an independent laboratory as a tenure-track investigator to expand her studies on interactions between pathogenic viruses and the host immune response. In 2011, Dr. Best was awarded a Presidential Early Career Award for Scientists and Engineers for her work on flavivirus suppression of innate immune responses.

 

Dr. Sonja Best, a virologist at NIAID's Rocky Mountain Laboratories, won a 2010 Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor bestowed by the U.S. government on scientists and engineers beginning their independent careers.

Research Group

Shelly J. Robertson, Ph.D., Staff Scientist
Kristin McNally, Ph.D., Molecular Biologist
Erin C. Foster, Ph.D., Postdoctoral Fellow
Kirk J. Lubick, M.S., Microbiologist
Abhilash Chiramel, Ph.D., Postdoctoral Fellow

Selected Publications

(View list in PubMed)

Taylor RT, Lubick KJ, Robertson SJ, Broughton JP, Bloom ME, Bresnahan WA, Best SM. TRIM79α, an interferon-stimulated gene product, restricts tick-borne encephalitis virus replication by degrading the viral RNA polymerase. Cell Host Microbe. 2011 Sep 15;10(3):185-96.

Laurent-Rolle M, Boer EF, Lubick KJ, Wolfinbarger JB, Carmody AB, Rockx B, Liu W, Ashour J, Shupert WL, Holbrook MR, Barrett AD, Mason PW, Bloom ME, García-Sastre A, Khromykh AA, Best SM. The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol. 2010 Apr;84(7):3503-15.

Valmas C, Grosch MN, Schümann M, Olejnik J, Martinez O, Best SM, Krähling V, Basler CF, Mühlberger E. Marburg virus evades interferon responses by a mechanism distinct from ebola virus. PLoS Pathog. 2010 Jan 15;6(1):e1000721.

Best SM. Viral subversion of apoptotic enzymes: escape from death row. Annu Rev Microbiol. 2008;62:171-92.

Park GS, Morris KL, Hallett RG, Bloom ME, Best SM. Identification of residues critical for the interferon antagonist function of Langat virus NS5 reveals a role for the RNA-dependent RNA polymerase domain. J Virol. 2007 Jul;81(13):6936-46.

Best SM, Morris KL, Shannon J, Robertson SJ, Mitzel DN, Park GS, Boer E, Wolfinbarger JB, Bloom ME. (2005). Inhibition of interferon-stimulated JAK-STAT signaling by a tickborne flavivirus and identification of NS5 as an interferon antagonist. J Virol. 2005 Oct;79(20):12828-39.

Visit PubMed for a complete publication list.

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Last Updated September 11, 2012

Last Reviewed September 11, 2012