Human papillomaviruses (HPVs) are the major cause of several cancers including cervical cancer, a leading cancer in women worldwide. Most infections are self limiting, but the sheer number of infections makes HPV-induced cancers very common. HPV infections can last for decades and cannot be cleared by currently available prophylactic vaccines. For this reason, understanding how HPV persistence is maintained in infected tissues is the critical next step in managing HPV-related diseases. Although HPVs infect epithelial keratinocytes exclusively, other cells in the stromal microenvironment, including fibroblasts, endothelial cells, and leukocytes, provide growth regulatory and innate immune signals that potentially affect the course of persistent HPV infection. We have found that the HPV oncoproteins E5 and E7 regulate overlapping sets of cellular factors that signal to stromal cells, most prominently the type I IFN and TGF pathways. This means that the virus can manipulate not just infected cells but also neighboring cells of the stromal microenvironment. We hypothesize that communication with stromal fibroblasts through the IFN and TGF pathways is crucial to the HPV life cycle. In this proposal we will determine 1) the importance of TGF and IFN signaling in stromal fibroblasts for the HPV life cycle. 2) How TGF and IFN signaling in keratinocytes impacts viral replication. 3) The molecular mechanism for regulation of IFNs and TGF by E5. The strength of this proposal is that it is the first to systematically investigate the role of the stromal microenvironment in the normal, evolved HPV life cycle and to focus on TGF and IFN in their functional setting as paracrine communication systems in the context of HPV infection. We will employ HPV replication in a three dimensional organotypic culture system as a functional readout in order to ensure our findings have relevance to the evolved HPV life cycle. At the end of this work, we will possess a more complete understanding of the interrelationship between innate immunity and growth factor signaling, and will thus gain insights into the problem of HPV persistence, as well as other conditions such as cancer, inflammatory diseases, and infections by other viruses.

Public Health Relevance

Persistent human papillomavirus (HPV) infection is the major risk factor for the development of cervical and certain other cancers. The ability of HPV to persist and multiply depends on growth factors and immune signals from cells surrounding the infected cell. This proposal will investigate how signals to and from the cells in the environment of the infection affect the ability of HPV to replicate, express its genes, and produce progeny virus particles.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI118904-04
Application #
9418575
Study Section
Virology - B Study Section (VIRB)
Program Officer
Natarajan, Ramya
Project Start
2015-08-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Hong, Shiyuan; Cheng, Shouqiang; Songock, William et al. (2017) Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification. J Virol 91:
Songock, William K; Kim, Seong-Man; Bodily, Jason M (2017) The human papillomavirus E7 oncoprotein as a regulator of transcription. Virus Res 231:56-75
Songock, William K; Scott, Matthew L; Bodily, Jason M (2017) Regulation of the human papillomavirus type 16 late promoter by transcriptional elongation. Virology 507:179-191
Dykes, Samantha S; Gao, ChongFeng; Songock, William K et al. (2017) Zinc finger E-box binding homeobox-1 (Zeb1) drives anterograde lysosome trafficking and tumor cell invasion via upregulation of Na+/H+ Exchanger-1 (NHE1). Mol Carcinog 56:722-734
Woodby, B; Scott, M; Bodily, J (2016) The Interaction Between Human Papillomaviruses and the Stromal Microenvironment. Prog Mol Biol Transl Sci 144:169-238