Tissue-specific gene expression during productive human papillomavirus 16 infection of cervical, foreskin, and tonsil epithelium

Sreejata Chatterjee, Sa Do Kang, Samina Alam, Anna C. Salzberg, Janice Milici, Sjoerd H. Van Der Burg, Willard Freeman, Craig Meyers

Research output: Contribution to journalArticle

Abstract

Epidemiological data confirm a much higher incidence of high-risk human papillomavirus 16 (HPV16)-mediated carcinogenesis of the cervical epithelium than for other target sites. In order to elucidate tissue-specific responses to virus infection, we compared gene expression changes induced by productive HPV16 infection of cervical, foreskin, and tonsil organotypic rafts. These rafts closely mimic persistent HPV16 infection, long before carcinogenesis sets in. The total number of gene expression changes varied considerably across the tissue types, with only 32 genes being regulated in common. Among them, we confirmed the Kelch-like family protein KLHL35 and the laminin-5 complex to be upregulated and downregulated, respectively, in all the three tissues. HPV16 infection induces upregulation of genes involved in cell cycle control, cell division, mitosis, DNA replication, and DNA damage repair in all the three tissues, indicative of a hyperproliferative environment. In the cervical and tonsil epithelium, we observe significant downregulation of genes involved in epidermis development, keratinocyte differentiation, and extracellular matrix organization. On the other hand, in HPV16-positive foreskin (HPV16 foreskin) tissue, several genes involved in interferon-mediated innate immunity, cytokine signaling, and cellular defenses were downregulated. Furthermore, pathway analysis and experimental validations identified important cellular pathways like STAT1 and transforming growth factor (TGF-) to be differentially regulated among the three tissue types. The differential modulation of important cellular pathways like TGF-1 and STAT1 can explain the sensitivity of tissues to HPV cancer progression. IMPORTANCE Although the high-risk human papillomavirus 16 infects anogenital and oropharyngeal sites, the cervical epithelium has a unique vulnerability to progression of cancer. Host responses during persistent infection and preneoplastic stages can shape the outcome of cancer progression in a tissue-dependent manner. Our study for the first time reports differential regulation of critical cellular functions and signaling pathways during productive HPV16 infection of cervical, foreskin, and tonsil tissues. While the virus induces hyperproliferation in infected cells, it downregulates epithelial differentiation, epidermal development, and innate immune responses, according to the tissue type. Modulation of these biological functions can determine virus fitness and pathogenesis and illuminate key cellular mechanisms that the virus employs to establish persistence and finally initiate disease progression.

Original languageEnglish (US)
Article numbere00915-19
JournalJournal of virology
Volume93
Issue number17
DOIs
StatePublished - Sep 1 2019

Fingerprint

Human papillomavirus 16
Foreskin
Papillomavirus Infections
tonsils
Palatine Tonsil
epithelium
Epithelium
Gene Expression
gene expression
infection
Down-Regulation
transforming growth factors
viruses
Transforming Growth Factors
Viruses
Innate Immunity
carcinogenesis
Genes
neoplasms
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Chatterjee, Sreejata ; Kang, Sa Do ; Alam, Samina ; Salzberg, Anna C. ; Milici, Janice ; Van Der Burg, Sjoerd H. ; Freeman, Willard ; Meyers, Craig. / Tissue-specific gene expression during productive human papillomavirus 16 infection of cervical, foreskin, and tonsil epithelium. In: Journal of virology. 2019 ; Vol. 93, No. 17.
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Tissue-specific gene expression during productive human papillomavirus 16 infection of cervical, foreskin, and tonsil epithelium. / Chatterjee, Sreejata; Kang, Sa Do; Alam, Samina; Salzberg, Anna C.; Milici, Janice; Van Der Burg, Sjoerd H.; Freeman, Willard; Meyers, Craig.

In: Journal of virology, Vol. 93, No. 17, e00915-19, 01.09.2019.

Research output: Contribution to journalArticle

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T1 - Tissue-specific gene expression during productive human papillomavirus 16 infection of cervical, foreskin, and tonsil epithelium

AU - Chatterjee, Sreejata

AU - Kang, Sa Do

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AU - Milici, Janice

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AU - Meyers, Craig

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AB - Epidemiological data confirm a much higher incidence of high-risk human papillomavirus 16 (HPV16)-mediated carcinogenesis of the cervical epithelium than for other target sites. In order to elucidate tissue-specific responses to virus infection, we compared gene expression changes induced by productive HPV16 infection of cervical, foreskin, and tonsil organotypic rafts. These rafts closely mimic persistent HPV16 infection, long before carcinogenesis sets in. The total number of gene expression changes varied considerably across the tissue types, with only 32 genes being regulated in common. Among them, we confirmed the Kelch-like family protein KLHL35 and the laminin-5 complex to be upregulated and downregulated, respectively, in all the three tissues. HPV16 infection induces upregulation of genes involved in cell cycle control, cell division, mitosis, DNA replication, and DNA damage repair in all the three tissues, indicative of a hyperproliferative environment. In the cervical and tonsil epithelium, we observe significant downregulation of genes involved in epidermis development, keratinocyte differentiation, and extracellular matrix organization. On the other hand, in HPV16-positive foreskin (HPV16 foreskin) tissue, several genes involved in interferon-mediated innate immunity, cytokine signaling, and cellular defenses were downregulated. Furthermore, pathway analysis and experimental validations identified important cellular pathways like STAT1 and transforming growth factor (TGF-) to be differentially regulated among the three tissue types. The differential modulation of important cellular pathways like TGF-1 and STAT1 can explain the sensitivity of tissues to HPV cancer progression. IMPORTANCE Although the high-risk human papillomavirus 16 infects anogenital and oropharyngeal sites, the cervical epithelium has a unique vulnerability to progression of cancer. Host responses during persistent infection and preneoplastic stages can shape the outcome of cancer progression in a tissue-dependent manner. Our study for the first time reports differential regulation of critical cellular functions and signaling pathways during productive HPV16 infection of cervical, foreskin, and tonsil tissues. While the virus induces hyperproliferation in infected cells, it downregulates epithelial differentiation, epidermal development, and innate immune responses, according to the tissue type. Modulation of these biological functions can determine virus fitness and pathogenesis and illuminate key cellular mechanisms that the virus employs to establish persistence and finally initiate disease progression.

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