Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Mymryk, Joseph

Abstract

In this thesis, I examined the effect of human papillomavirus (HPV) on the proinflammatory IL-18 cytokine pathway in head and neck cancers. I investigated the expression and methylation of genes associated with this pathway using The Cancer Genome Atlas (TCGA) data. In HPV+ cancers, IL18, CASP1, and AIM2 were downregulated, while IL18BP was upregulated compared to HPV- cancers and adjacent non-cancerous tissues, and IL18’s promoter was significantly more methylated. I compared HPV+ and HPV- head and neck cancer cell lines for expression of RNA and protein levels of IL-18 and IL-18BP by qPCR, western blot, and ELISA. IL-18 mRNA and protein levels were lower in HPV+ cells, while IL-18BP mRNA was higher. The E7 protein from most HPV types repressed an IL18 luciferase reporter and this required conserved region 3 of HPV16. Repression of IL-18 mediated inflammation may help HPV evade the immune system and contribute to chronic infection.

Summary for Lay Audience

Human papillomaviruses (HPV) are an expanding cause of cancer in the global theater of human disease and are responsible for ~5% of cancers world-wide. HPV is the root cause of practically all cervical cancers, a large number of anogenital cancers, and at the focus of this thesis, a rising number of head and neck cancers. These HPV+ cancers are biologically unique when compared to their HPV- counterparts. They express the viral HPV cancer causing genes early gene 6 (E6) and early gene 7 (E7) integrated into their own genome. These viral genes encode proteins that disrupt our cell’s ability to control their replication, repress their ability to die in response to cancerous growth, and signal the immune system that they are infected. This allows HPV infected cells to divide uncontrollably and avoid the immune system. The avoidance of the immune system is important to HPV’s ability to cause cancer, as the immune system normally destroys cells within a state of uncontrolled replication. We identified and began to study an additional way by which HPV avoids the immune system, through the suppression of the interleukin-18 (IL-18) inflammatory pathway. IL-18 is an important component of the immune system within our skin, and functions by activating immune cells with anti-viral and anti-cancer properties. As HPV infects skin cells, avoiding the IL-18 proinflammatory response is an important barrier to surpass and may contribute to the ability of this virus to establish and maintain infection. In this thesis, I explore the impact of HPV on expression of IL-18, components of the protein complexes that activate it, and its suppressor IL-18 binding protein (IL-18BP) in head and neck cancers. I found a consistent and targeted downregulation of the IL-18 pathway, which I attributed to HPV E7. Suppression of this inflammatory pathway has significant implications on the establishment and maintenance of infection by HPV and could contribute to the ability of HPV to cause head and neck cancer.

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