Michelle Ozbun's Laboratory

Michelle A. Ozbun, Ph.D.

The Maralyn S. Budke Endowed Professor of Viral Oncology

Molecular Genetics and Microbiology
MSC08 46601 University of New Mexico
Albuquerque, NM 87131-0001
 
Office: Cancer Research Facility (CRF) 317A
Tel: (505) 272-4950
Fax: (505) 272-6029
E-mail: mozbun@salud.unm.edu

Keywords: Papillomavirus, HPV, virus infection, skin, wart, epithelium, cancer, cervix, cervical cancer, skin cancer, anogenital cancer, head-and-neck 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 or if you are interested in post-doctoral opportunities


Founded in 1889, the University of New Mexico sits on the traditional homelands of the Pueblo of Sandia. The original peoples of New Mexico – Pueblo, Navajo, and Apache – since time immemorial, have deep connections to the land and have made significant contributions to the broader community statewide. We honor the land itself and those who remain stewards of this land throughout the generations and also acknowledge our committed relationship to Indigenous peoples. We gratefully recognize our history.

Core laboratory values:  Our lab has a longstanding commitment to diversity and inclusion, which we believe fosters an environment of health, well-being, scientific creativity and excellence.  We strive to maintain an lab home that is free from all forms of discrimination and harassment.  


Research Interests

Papillomaviruses (PVs) are etiologic agents of numerous benign and malignant tumors of the skin and mucosa.  Benign warts include common, plantar, anal, genital and respiratory warts (or papillomas).  Malignant tumors include anogenital cancers, such as penile, anal, and cervical carcinomas and adenocarcinomas, a growing proportion of oropharyngeal cancers, and certain non-melanoma skin malignancies. 

The focus of research in my lab is on the differentiation-dependent replicative cycles of PVs (Fig. 1) and the mechanisms by which the replicative cycles can become disrupted and progress to malignancies.  Primarily our group focuses on human papillomaviruses (HPVs), but we also study rhesus and mouse papillomaviruses as model systems. To support viral replication in the laboratory, we use the organotypic (raft) tissue culture system to cultivate differentiating epithelium.

We are specifically interested in three areas of research with respect to HPV infections and cancer:  (i) Investigating the molecular specifics of viral interaction with host keratinocytes leading to virion uptake (Fig. 2); (ii) Identifying the step(s) of viral infection at which host range and tissue tropism are demonstrated and permit or deny the establishment of viral persistence; (iii) Defining the mechanisms by which HPV oncoprotein expression is regulated, in an effort to better understand epithelial biology and cancer progression.  

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Fig. 1. The full papillomavirus replicative cycle requires stratifying and differentiating epithelium.  The five canonical steps of virus infection as shown numbered: 1-attachment, 2-entry, 3-genome replication, 4-assembly, 5-release.  Due to the dependence of PV replication on epithelial differentiation, viral genome replication (step 3) occurs in three distinct stages (steps 3i, ii, ii).  These include: (3i) genome establishment, where the incoming viral genome is replicated to 10-50 copies per nucleus;  (3ii) maintenance, wherein viral genomes are replicated with cellular DNA and partitioned into daughter cells mediated by E2 linkage to mitotic chromosomes; and (3iii) amplification in the upper suprabasal cell layers in preparation for the assembly of progeny virions.  These three phases of vDNA replication, as well as early and late viral gene expression, are separated temporally and spatially in the productively infected epithelium (modified from Young et al. 2019).  Image created with BioRender.


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Fig. 2.  Proposed model for HPV extracellular interactions in a dynamic wounded microenvironment where virions are associated with DCCs.  (A). Natural processes that occur in the absence of HPV.  The basal edges of epithelial cells contact the ECM consisting of collagens, elastins, fibronectins, and laminins. LN332 interacts with Sdc1, CD151 tetraspanin and a6b4 integrin on the basal cell to provide cell anchorage to the ECM/basement membrane, termed the hemidesmosome.  (i.) Proprotein convertases, like furin, activate MMPs and ADAM sheddases (ii), which catalyze the release or “shedding” of membrane-bound GFs and the protein ectodomains of HSPG, including Sdc1 and Sdc4 (dotted arrows).  (iii.) HSPG in the plasma membrane and ECM act as local depots for soluble GFs and other bioactive molecules.  (iv.) Soluble complexes containing GFs and HSPGs are liberated by heparanases and proteolytic processing of LN332.  (v.) Soluble GF complexes bind to GFRs and activate intracellular signaling cascades.  EGFR-mediated Src signaling activates the A2t to transport to the plasma membrane surface.  A2t and CD151 regulate EGFR endocytosis.   (B).  Whenpresent, HPVs hijack the normal processes of HSPG decoration with GFs and their release from the cells.  By virtue of HPV particle interaction with HS, KLK8 cleaves L1, furin processes L2 and promotes sheddase-mediated release of HSPG- and GF-bound HPV.  These functions foster HPV decoration with HS and GFs (iv) and signaling, leading to virus interaction with the receptor complex (v)(vi.) HPV virions may associate with soluble HS-GF complexes in the wound and in vivo may also arrive in the wound milieu with the ability to induce signaling to mobilize the receptor complex.  Image created with BioRender.  From Ozbun 2019.

Lab Members Contact Information:

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kiersten_berggren.jpgKiersten B.

 

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amira2.jpgAmira Z.

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rosa4.jpgRosa S.

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virginie.jpgVirginie B.

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adrian2.jpgAdrian L.

 

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jesse2.jpegJesse Y.

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Mais A.

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matilde.jpgMatilde J.

 

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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. 

Selected Publications

Link to PubMed

Young, J.M., Zine El Abidine, A., Gómez-Martinez, R.A., Ozbun, M.A. 2019.  The Known and Potential Intersections of Rab-GTPases in Human Papillomavirus Infections. Front Cell Dev Biol.7:139. doi: 10.3389/fcell.2019.00139  https://www.frontiersin.org/articles/10.3389/fcell.2019.00139/full

Berggren, K.L., Restrepo Cruz ,S., Hixon, M.D., Cowan, A.T., Keysar, S.B., Craig, S., James, J., Barry, M., Ozbun, M.A., Jimeno, A., McCance, D.J., Beswick, E.J., Gan, G.N.  2019.  MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma. Oncogene. 2019 Epub ahead of print.  https://www.nature.com/articles/s41388-019-0945-9

Ozbun M.A.  2019. Extracellular events impacting human papillomavirus infections: Epithelial wounding to cell signaling involved in virus entry.  Papillomavirus Res. 7:188-192. https://doi.org/10.1016/j.pvr.2019.04.009

Muñoz J.P., Carrillo-Beltrán D., Aedo-Aguilera V., Calaf G.M., León O., Maldonado E., Tapia J.C., Boccardo E.,Ozbun M.A., Aguayo F. 2018. Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells. Front Microbiol. 9:3022.

Brand T., S. Hartmann, N. Bhola, H. Li, Yan Zang, R. O'Keefe, M. Ranall, S. Bandyopadhyay, M. Soucheray, N. Krogan, C. Kemp, U. Duvvuri, T. LaVallee, D. Johnson, M. Ozbun, J. Bauman, and J. Grandis. 2018.  Crosstalk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer.  Cancer Research, 78(9):2383-2395.

Staquicini DI, Rangel R, Guzman-Rojas L, Staquicini FI, Dobroff AS, Tarleton CA, Ozbun MA, Kolonin MG, Gelovani JG, Marchiò S, Sidman RL, Hajjar KA, Arap W, Pasqualini R.  2017. Intracellular targeting of annexin A2 inhibits tumor cell adhesion, migration, and in vivo grafting. Sci Rep. 7(1):4243. PMID: 28652618

Klionsky DJ, et al.  2016 Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12(1):1-222.

Surviladze, Z., R. T. Sterk and M. A. Ozbun. 2015. The interaction of human papillomavirus type 16 particles with heparan sulfate and syndecan-1 molecules in the keratinocyte extracellular matrix plays an active role in infection. J. Gen. Virol. Aug;96(8):2232-41.

Ozbun, M. A. and Patterson, N. A. 2014. Using Organotypic (Raft) Epithelial Tissue Cultures for the Biosynthesis and Isolation of Infectious Human Papillomaviruses. Curr. Protoc. Microbiol. 34:B:14B.3:14B.3.1–14B.3.18. 

Wei, L., Griego, A.M., Chu, M. and M.A. Ozbun. 2014. Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes, Published ahead of print Carcinogenesis, 35(10):2373-81.

Tyler M., Tumban E., Dziduszko A., Ozbun M.A., Peabody D.S., B. Chackerian. 2014. Immunization with a consensus epitope from human papillomavirus L2 induces antibodies that are broadly neutralizing, Vaccine. Jul 23;32(34):4267-74. 

Dziduszko, A. and  M.A. Ozbun. 2013. Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes, J. Virol., 87(13):7502-7515.

Surviladze, Z., R. T. Sterk, S. A. De Haro, and M. A. Ozbun. 2013. Cellular Entry of Human Papillomavirus Type 16 Involves Activation of the PI3K/Akt/mTOR Pathway and Inhibition of Autophagy. J Virol, 87:2508-2517.

Surviladze Z, Dziduszko A, and M. A. Ozbun.  2012.  Essential roles for soluble virion-associated heparan sulfonated proteoglycans and growth factors in human papillomavirus infections.  PLoS Pathog. Feb;8(2):e1002519. Epub 2012 Feb 9.

Campos SK, Chapman JA, Deymier MJ, Bronnimann MP, and M. A. Ozbun.  2012. Opposing effects of bacitracin on human papillomavirus type 16 infection: enhancement of binding and entry and inhibition of endosomal penetration.  J Virol. Apr;86(8):4169-81. Epub 2012 Feb 15.

Bergant Marusic, M., Ozbun, M. A, Campos, S. K., Myers, M. P., L. Banks.  2012. Human Papillomavirus L2 facilitates viral escape from late endosomes via Sorting Nexin 17.  Traffic, 13(3):455-67. 

H. Song, P. Moseley, S. L. Lowe, and M. A. Ozbun. 2010. Inducible heat shock protein 70 enhances HPV31 viral genome replication and virion production during the differentiation-dependent life cycle in human keratinocytes. Virus Res.  Jan;147(1):113-22. Epub 2009 Nov 5.

Wei, L., P.E. Gravitt, H. Song, A. Maldonado, and M. A. Ozbun. 2009. Nitric oxide induces early viral transcription coincident with increased DNA damage and mutation rates in human papillomavirus infected cells. Cancer Res. 69: 4878-4884.

Campos, S. K. and M. A. Ozbun. 2009. 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. doi:10.1371/journal.pone.0004463

Tomaic, V., D. Gardiol, P. Massimi, M. Ozbun, M. Myers, and L. Banks. 2009. Human and Primate Tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogene 28(1):1-8.

J.L. Smith, D. S. Lidke, and M. A. Ozbun. 2008. Virus activated filopodia promote human papillomavirus type 31 uptake from the extracellular matrix. Virology, 381:16-21. **Cover art for journal issue.

J. L. Smith, S.K. Campos, A. Wandinger-Ness, and M. A. Ozbun.  2008. 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.

J.L. Smith, S.K. Campos and M. A. Ozbun. 2007. Human papillomavirus type 31 uses a caveolin 1- and dynamin 2-mediated entry pathway for infection of human keratinocytes. J. Virology, 81:9922-9931.

Ozbun, M. A., S. K. Campos, and J. L. Smith. 2007.  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.

Y. Wu, S. K. Campos, G. P. Lopez, M. A. Ozbun, L. A. Sklar, T. Buranda, 2007. The Development of Quantum Dot Calibration Beads and Quantitative Multicolor Bioassays in Flow Cytometry and Microscopy, Anal. Biochem. 364(2):180-92.

A. F. Deyrieux, G. Rosas-Acosta, M. A. Ozbun and Van G. Wilson.  2007. Sumoylation dynamics during keratinocyte differentiation, J. Cell Sci. 120:125-36.

N. A. Patterson, J. L. Smith, M. A. Ozbun.  2005. Human papillomavirus type 31b infection of human keratinocytes does not require heparan sulfate.  J. Virology, 79: 6838-6847.

P. F. Lambert, M. A. Ozbun, A. Collins, S. Holmgren, D. Lee, and T. Nakahara. 2005. Using an immortalized cell line to study the HPV life cycle in organotypic "raft" cultures. Methods Mol Med. 119:141-55.

S.C. Holmgren, N. A. Patterson, M. A. Ozbun, P. F. Lambert.  2005. The minor capsid protein, L2, contributes to multiple steps in the papillomaviral life cycle. J. Virology, 79:3938-3948.

J. H. Lee, S. M. P. Yi, M. E. Anderson, K. L. Berger, M. J. Welsh, A. J. Klingelhutz, and M. A. Ozbun. 2004. Propagation of Infectious Human Papillomavirus Type 16 Using Adenovirus and Cre/LoxP Mechanism.  Proc. Natl. Acad. Sci., 101:2094-2099.

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.