Matthew Wiebe, Ph.D.

Assistant Professor
University of Nebraska-Lincoln
School of Veterinary and Biomedical Sciences
139 Morrison Center
Lincoln, NE 68583-0900

Telephone: (402) 472-4154
Fax: (402) 472-3323
E-mail: mwiebe2@unl.edu

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

Wang J, Alexander J, Wiebe MS, Jones C. Bovine herpesvirus 1 productive infection stimulates inflammasome formation and caspase 1 activity. Virus Res. 2014 Mar 19;PubMed PMID: 24657787.

Jamin A, Wicklund A, Wiebe MS. Cell and Virus Mediated Regulation of the Barrier-to-Autointegration Factor's Phosphorylation State Controls its DNA Binding, Dimerization, Subcellular Localization, and Antipoxviral Activity. J Virol. 2014 Mar 5;PubMed PMID: 24600006.

Ibrahim N, Wicklund A, Jamin A, Wiebe MS. Barrier to autointegration factor (BAF) inhibits vaccinia virus intermediate transcription in the absence of the viral B1 kinase. Virology. 2013 Sep;444(1-2):363-73. PubMed PMID: 23891157; PubMed Central PMCID: PMC3755115.

Greseth MD, Boyle KA, Bluma MS, Unger B, Wiebe MS, Soares-Martins JA, Wickramasekera NT, Wahlberg J, Traktman P. Molecular genetic and biochemical characterization of the vaccinia virus I3 protein, the replicative single-stranded DNA binding protein. J Virol. 2012 Jun;86(11):6197-209. PubMed PMID: 22438556; PubMed Central PMCID: PMC3372221.

Ibrahim N, Wicklund A, Wiebe MS. Molecular characterization of the host defense activity of the barrier to autointegration factor against vaccinia virus. J Virol. 2011 Nov;85(22):11588-600. PubMed PMID: 21880762; PubMed Central PMCID: PMC3209281.

Cox JL, Mallanna SK, Ormsbee BD, Desler M, Wiebe MS, Rizzino A. Banf1 is required to maintain the self-renewal of both mouse and human embryonic stem cells. J Cell Sci. 2011 Aug 1;124(Pt 15):2654-65. PubMed PMID: 21750191; PubMed Central PMCID: PMC3138706.

Wiebe MS, Nichols RJ, Molitor TP, Lindgren JK, Traktman P. Mice deficient in the serine/threonine protein kinase VRK1 are infertile due to a progressive loss of spermatogonia. Biol Reprod. 2010 Jan;82(1):182-93. PubMed PMID: 19696012; PubMed Central PMCID: PMC2802121.

Wiebe MS, Traktman P. Poxviral B1 kinase overcomes barrier to autointegration factor, a host defense against virus replication. Cell Host Microbe. 2007 May 17;1(3):187-97. PubMed PMID: 18005698; PubMed Central PMCID: PMC1978190.

Nichols RJ*, Wiebe MS*, 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. PubMed PMID: 16495336; PubMed Central PMCID: PMC1446082.

*These authors contributed equally to this work.

Bernadt CT, Nowling T, Wiebe MS, Rizzino A. NF-Y 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. PubMed PMID: 16128003.

Wiebe MS, Nowling TK, Rizzino A. Identification of novel domains within Sox-2 and Sox-11 involved in autoinhibition of DNA binding and partnership specificity. J Biol Chem. 2003 May 16;278(20):17901-11. PubMed PMID: 12637543.

Wiebe MS, Wilder PJ, Kelly D, Rizzino A. Isolation, characterization, and differential expression of the murine Sox-2 promoter. Gene. 2000 Apr 4;246(1-2):383-93. PubMed PMID: 10767561.

Nowling TK, Johnson LR, Wiebe MS, Rizzino A. Identification of the transactivation domain of the transcription factor Sox-2 and an associated co-activator. J Biol Chem. 2000 Feb 11;275(6):3810-8. PubMed PMID: 10660531.

Education

B.S. 1998
University of Nebraska-Omaha, Omaha, NE

Ph.D. 2003
University of Nebraska Medical Center, Omaha, NE  (Eppley Institute for Research in Cancer and Allied Diseases and the Dept. of Pathology & Microbiology)

Professsional Positions

2009-present Assistant Professor, University of Nebraska - Lincoln, Lincoln, NE.

2003-2009 Postdoctoral Fellow, Medical College of Wisconsin, Department of Microbiology and Molecular Genetics, Milwaukee, WI. Advisor: Paula Traktman, Ph.D.

1998-2003 Graduate Training, University of Nebraska Medical Center, Department of Cell Biology, Omaha, NE. Advisor: Angie Rizzino, Ph.D.

Honors and Professional Affiliations

2004-2006 Postdoctoral Training Grant - Great Lakes Regional Center of Excellence for Biodefense and Emerging Disease

2010-2012 K22 Award from the NIAID entitled “BAF: An Intrinsic Host Defense Responsive to Foreign DNA”

Member of: American Association for the Advancement of Science; American Society for Virology

Lab Members