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TARGETING LANGERHANS CELLS:
A HUMAN PAPILLOMAVIRUS TYPE 16 IMMUNE EVASION MECHANISM
by
Laura Marie Fahey
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR MICROBIOLOGY AND IMMUNOLOGY)
May 2009
Copyright 2009 Laura Marie Fahey
Object Description
| Title | Targeting Langerhans cells: a human papillomavirus type 16 immune evasion mechanism |
| Author | Fahey, Laura Marie |
| Author email | lfahey@usc.edu; laura.fahey@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Microbiology & Immunology |
| School | Keck School of Medicine |
| Date defended/completed | 2009-03-20 |
| Date submitted | 2009 |
| Restricted until | Restricted until 28 Apr. 2010. |
| Date published | 2010-04-28 |
| Advisor (committee chair) | Kast, W. Martin |
| Advisor (committee member) |
Schonthal, Axel Epstein, Alan |
| Abstract | High-risk human papillomaviruses (HPV) infect the epithelial layer of cervical mucosa and are causally associated with the generation of cervical cancer. Although most women infected with HPV clear their lesions, the long latency period from infection to resolution indicates that HPV has evolved immune escape mechanisms. Langerhans cells (LC) are the resident antigen-presenting cells at the site of infection and therefore are responsible for initiating an immune response against HPV. However, LC exposed to HPV16L1L2 virus-like particles do not induce an HPV-specific T cell response, suggesting that LC are targeted by HPV to evade immune detection. Herein we describe a novel immune escape mechanism of HPV16 that targets LC function and identify therapeutic compounds to overcome the HPV16 induced suppression of LC. We demonstrate that LC incubated with HPV16L1L2 virus-like particles up-regulate phosphoinositide 3-kinase activation while down-regulating mitogen-activated protein kinase and nuclear factor-κB pathways. When phosphoinositide 3-kinase activation is inhibited and LC are subsequently exposed to HPV16L1L2 virus-like particles, LC initiate a potent HPV-specific response, revealing that phosphoinositide 3-kinase activation in LC is an escape mechanism utilized by HPV16. Importantly, we also show that the minor capsid protein L2 is responsible for the induction of this immune escape of HPV16 through the manipulation of LC. Additionally, using pulldown assays we demonstrate that the N-terminus of L2 associates with annexin A2. Inhibiting the interaction between HPV16 L2 and annexin A2 disrupts the internalization of HPV16L1L2 virus-like particles by LC, indicating that annexin A2 is the L2 receptor for HPV16, which likely initiates the immune escape mechanism of HPV16 through LC.; Furthermore, we identify two molecules, 3M-002 (TLR8 agonist) and resiquimod (TLR8/7 agonist) that can overcome the phenotypic and functional suppression of LC previously exposed to HPV16L1L2 virus-like particles. Collectively, our studies delineate a novel HPV16 immune escape mechanism and direct the future development of therapeutics for treatment of HPV infections and HPV-induced cervical lesions. |
| Keyword | HPV; Langerhans cells; immune evasion; cell mediated immunity |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2141 |
| Rights | Fahey, Laura Marie |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Fahey-2664 |
| Archival file | uscthesesreloadpub_Volume29/etd-Fahey-2664.pdf |
Description
| Title | Page 1 |
| Full text | TARGETING LANGERHANS CELLS: A HUMAN PAPILLOMAVIRUS TYPE 16 IMMUNE EVASION MECHANISM by Laura Marie Fahey A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR MICROBIOLOGY AND IMMUNOLOGY) May 2009 Copyright 2009 Laura Marie Fahey |
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