Matthew Wiebe, Ph.D.
Research Program: One of the most fundamental questions in the field of immunology is how our immune system identifies an invading pathogen as “foreign” rather than “self”. When this decision is made correctly growth of the virus or bacteria can kept at a minimum. However, failure to recognize an invader extends the amount of damage it may produce or, if self is incorrectly regarded as foreign, then autoimmune disease occurs. While significant progress has been made toward identifying viral and bacterial components which are found to be “foreign” and activate the immune system, much remains to be learned. In the last decade it has become increasingly clear that our immune system is not only activated by proteins present in pathogens, but RNA and DNA as well. My research focus in this area of host-pathogen interaction is two-fold. First, it is to understand the molecular sensors utilized by the cell to identify and respond to foreign DNA. Second, it is to characterize the methods viruses use to evade these DNA-specific immune defenses. To accomplish these two goals, I study vaccinia virus, which possesses a large DNA genome. Vaccinia is a member of the poxvirus family, and is closely related to the smallpox and monkeypox viruses. Vaccinia was given as a live vaccine against smallpox during the World Health Organization’s successful campaign to eradicate smallpox 30 years ago. While vaccinia is no longer given as a routine vaccine, further study of this viral cousin of smallpox is warranted for at least two general reasons. First, a greater understanding of poxvirology is of biomedical relevance, as highlighted by the recent monkeypox outbreak in the U.S. as well as the potential use of smallpox as an agent of bioterrorism. Second, vaccinia possesses a large protein repertoire capable of interfering with our immune systems at multiple levels. Therefore, vaccinia provides a powerful model to further examine host-pathogen interactions, potentially revealing details important not only for poxviruses, but other DNA viruses as well. My research with vaccinia virus has led to the discovery that during replication of the viral DNA, vaccinia must evade a cellular protein called BAF, which would otherwise bind to the viral DNA and inhibit its replication. The virus evades BAF by inactivating its DNA binding capability via phosphorylation of BAF by a viral kinase referred to as B1 (Figure 1). These studies indicate that BAF is a novel type of host defense against viral DNA, which may in fact extend to other sources of foreign DNA, including other viruses and potentially bacteria. Furthermore, BAF is expressed in most cell types and thus is likely to be a general DNA-specific defense in a wide range of tissues. In my laboratory, we have three primary aims. 1) We will continue to characterize BAF’s impact on vaccinia DNA replication as well as examine how this poxvirus deals with other known DNA sensor proteins. 2) We will explore the question of whether BAF is capable of responding to other sources of foreign DNA including plasmids or during infection with other viruses. 3) We will examine the cellular regulation of BAF, which would be needed to keep BAF in check in the absence of an infection. We will also address the question of whether BAF activates downstream inflammatory signaling cascades to alert the cell to the presence of an intruder, thus augmenting the immune response against infection. Selected Recent Publications: 1. Nowling TK, Johnson LJ, Wiebe MS, and Rizzino, A: Identification of the Transactivation Domain of the Transcription Factor Sox-2 and an Associated 2. Wiebe MS, Wilder PJ, Kelly D, and Rizzino, A: Isolation, Characterization, and 3. Wiebe MS, Nowling TK, and Rizzino A: Identification of Novel Domains within Sox-2 and Sox-11 Involved in Autoregulation of DNA Binding and Partnership Specificity. J Biol Chem 2003 May 16;278(20):17901-11. 4. Bernadt C, Nowling TK, Wiebe MS, and Rizzino A. NF-gamma behaves as a bifunctional transcription factor that can stimulate or repress the FGF-4 promoter in an enhancer-dependent manner. Gene Expr. 2005;12(3):193-212. 5. Nichols RJ*, Wiebe MS*, and Traktman P. The Vaccinia-related Kinases Phosphorylate the N-Terminus of BAF, Regulating Its Interaction with DNA and Its Retention in the Nucleus. Mol Biol Cell 2006 May;17(5):2451-64. 6. Wiebe MS and Traktman P. Poxviral B1 Kinase Overcomes Barrier to Autointegration Factor, a Host Defense Against Virus Replication. Cell: Host and Microbe 2007 May 16;1(3):187-197. 7. Wiebe MS, Nichols RJ, Molitor TP, Lindgren JK, and Traktman P. Mice Deficient In the Serine/Threonine Protein Kinase VRK1 Are Infertile Due to a Progressive Loss of Spermatogonia. Biol Reprod 2009 August 19 [epub date]
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