Michelle A. Ozbun, Ph.D.
Molecular Genetics and Microbiology
MSC08 4660
1 University of New Mexico
Albuquerque, NM 87131-0001
Office: CRF 303
Tel: (505) 272-4950
Fax: (505) 272-9912
E-mail: mozbun@salud.unm.edu
Keywords: Papillomavirus, HPV, virus infection, skin, wart, epithelium, cancer, cervix, cervical cancer, skin cancer, anogenital cancer, penile cancer, head-and-neck cancer, breast cancer, animal model, rhesus macaque, tobacco, nitric oxide, heat shock proteins, chaperone, co-factors, basic science, pre-clinical models, microbicides, vaccine, virus-cell interactions, epithelial biology, cancer biology, virology
Please visit the OZBUN LAB HOMEPAGE for more information
Research Interests
Papillomaviruses (PVs) are etiologic agents of a number of benign and malignant tumors of the skin and mucosa. These include anogenital cancers, such as penile, anal, and cervical carcinomas and adenocarinomas, some cancers of the head-and-neck, and certain non-melanoma skin malignancies. Limited data suggest that HPV might be involved in some breast cancers.
The focus of research in our lab is on the differentiation-dependent life cycles of PVs and how the life cycles are disrupted leading to malignancies. Primarily our group focuses on human papillomaviruses (HPVs), but we also study bovine papillomavirus type 1 (BPV1) as a model system. We are also developing a rhesus monkey model of papillomavirus-induced genital infection and disease (info). This virus causes genital neoplasias and malignancies in rhesus monkeys and we determining if this system can be used to study the pathogenesis of PV-induced anogenital lesions in vivo.
PVs require differentiating epithelium in order to complete their viral life cycles and we use the organotypic (raft) tissue culture system to cultivate differentiating epithelium and study the life cycles of PVs in the laboratory.
A recent advance by our colleagues at the University of Wisconsin-Madison called the high-yield production (HiP) method allows us to purify very high titers of infectious PVs (Pyeon, D., P.F. Lambert, and P. Ahlquist, Proc Natl Acad Sci USA, 102:9311-9316, 2005.)
The long-term goals of our research program are to elucidate the cellular and viral mechanisms that regulate the life cycle of PVs, and to understand the delicate virus-cell interactions that can become unbalanced, leading to malignancy. We are specifically interested in three areas of research with respect to PV infections and cancer: (i) Investigating the strategies of initial PV replication upon infection and the mechanisms for establishment of viral persistence; (ii) Identifying the step(s) of PV infection at which host range and tissue tropism are demonstrated; (iii) Analyzing potential common pathways used by various co-factors, which cooperate with HPVs in causing cancers.
A model for PV infection and life cycle in a stratified epithelium. The three stages of viral genome replication are indicated; major viral functions and presence of potential cellular attachment moieties in the differentiated epithelial tissues are noted at the right. Infection of basal cells is likely necessary for the establishment of viral persistence in these putative stem cells. Stage I involves the initial establishment of the viral genome at low copy number (10-50 copies per cell) in an infected cell. Stage II is the replication of genomes along with cellular DNA in preparation for cell division. As cells migrate through the epithelium, they undergo a complex program of differentiation. Stage III viral DNA amplification occurs in suprabasal cells and is the vegetative DNA replication phase. Late gene expression is restricted to the upper, differentiated layers of the epithelium; concurrent viral DNA amplification and late gene expression lead to viral DNA packaging and virion morphogenesis. Many HSPGs including syndecans and glypicans are expressed on keratinocyte membranes throughout the epidermis and mucosa. Alpha-6 integrin expression is generally restricted to basal keratinocytes where it can pair with alpha-4 integrin attaching the keratin cytoskeleton to the basement membrane, in some cases by binding to laminin 5. Laminin 5 is an extracellular molecule found in the basement membrane where it anchors cells. During wound healing laminin 5 is secreted into the leading edge of the wound (indicated by *). See references and figure in (Ozbun, Campos and Smith, 2007).
Information about post-doctoral positions in the Ozbun lab.
Patents
U.S. Patent Serial No. 6,110,663: Methods for detecting, titering, and determining susceptibility to papillomavirus.
U.S. Patent Serial No. 7,285,386: RhPV as a model for HPV-induced cancers. See the description our Lab Homepage under " Our Model Systems".
Selected Publications
Song, H., P. Moseley, S. L. Lowe, M. A. Ozbun. Inducible heat shock protein 70 enhances HPV31 viral genome replication and virion production during the differentiation-dependent life cycle in human keratinocytes. Virus Res., in press 2009.
Wei, L., P.E. Gravitt, H. Song, A. Maldonado, and M. A. Ozbun. Nitric oxide induces early viral transcription coincident with increased DNA damage and mutation rates in human papillomavirus infected cells. Cancer Res. 69: 4878-4884, 2009.
Campos, S. K. and M. A. Ozbun. Two Highly Conserved Cysteine Residues in Human Papillomavirus Type 16 L2 Form an Intramolecular Disulfide Bond and are Critical for Infectivity in Human Keratinocytes. PLoS ONE 4(2): e4463, 2009. doi:10.1371/journal.pone.0004463
Tomaic, V., D. Gardiol, P. Massimi, M. Ozbun, M. Myers, and L. Banks. Human and Primate Tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogene 28(1):1-8, 2009.
J.L. Smith, D. S. Lidke, and M. A. Ozbun. Virus activated filopodia promote human papillomavirus type 31 uptake from the extracellular matrix. Virology, 381:16-21, 2008. **Cover art for journal issue.
J. L. Smith, S.K. Campos, A. Wandinger-Ness, and M. A. Ozbun. Caveolin-1 dependent infectious entry of human papillomavirus type 31 in human keratinocytes proceeds to the endosomal pathway for pH-dependent uncoating. J. Virology, 82:9505-9512, 2008.
J.L. Smith, S.K. Campos and M. A. Ozbun. Human papillomavirus type 31 uses a caveolin 1- and dynamin 2-mediated entry pathway for infection of human keratinocytes. J. Virology, 81:9922-9931, 2007
Ozbun, M. A., S. K. Campos, and J. L. Smith. The Early Events of Human Papillomavirus Infections: Implications for Regulation of Cell Tropism and Host Range, In New Strategies for Human Papillomavirus Gene Regulation and Transformation, B. Norrild (Ed.), Research Signpost, Kerala, India, pp 69-122, 2007.
Y. Wu, S. K. Campos, G. P. Lopez, M. A. Ozbun, L. A. Sklar, T. Buranda, The Development of Quantum Dot Calibration Beads and Quantitative Multicolor Bioassays in Flow Cytometry and Microscopy, Anal. Biochem. 364(2):180-92, 2007.
A. F. Deyrieux, G. Rosas-Acosta, M. A. Ozbun and Van G. Wilson. Sumoylation dynamics during keratinocyte differentiation, J. Cell Sci. 120:125-36, 2007.
N. A. Patterson, J. L. Smith, M. A. Ozbun. Human papillomavirus type 31b infection of human keratinocytes does not require heparan sulfate. J. Virology, 79: 6838-6847, 2005.
P. F. Lambert, M. A. Ozbun, A. Collins, S. Holmgren, D. Lee, and T. Nakahara. Using an immortalized cell line to study the HPV life cycle in organotypic "raft" cultures. Methods Mol Med. 2005;119:141-55.
S.C. Holmgren, N. A. Patterson, M. A. Ozbun, P. F. Lambert. The minor capsid protein, L2, contributes to multiple steps in the papillomaviral life cycle. J. Virology, 79:3938-3948, 2005.
J. H. Lee, S. M. P. Yi, M. E. Anderson, K. L. Berger, M. J. Welsh, A. J. Klingelhutz, and M. A. Ozbun. Propagation of Infectious Human Papillomavirus Type 16 Using Adenovirus and Cre/LoxP Mechanism. Proc. Natl. Acad. Sci., 101:2094-2099, 2004.
Ozbun, M. A. 2002. Human papillomavirus type 31b infection of human keratinocytes and the onset of early transcription, J. Virol, 76:11291-11300.
Ozbun, M. A. 2002. Infectious human papillomavirus type 31b: purification and infection of an immortalized human keratinocyte cell line, J. Gen. Virol, 83:2753-2763.
Steele, B. K., C. Meyers, and M. A. Ozbun. 2002. Variable expression of some "housekeeping" genes during human keratinocyte differentiation, Anal. Biochem., 307:341-347.