Dataset Information

Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections.

ABSTRACT: HPVs are DNA viruses include approximately 450 types that are classified into 5 genera (α-, β-, γ-, μ-, and ν-HPV). The γ- and β-HPVs are present in low copy numbers in healthy individuals; however, in patients with an inborn error of immunity, certain species of β-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either typical or atypical. Manifestations of typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to β-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, to RNA extracted from normal-appearing skin and wart samples of patients with typical EV to explore the viral and human genetic determinants. In 26 patients, 9 distinct biallelic mutations were detected in TMC6, TMC8, and CIB1, 7 of which are previously unreported to our knowledge. Additionally, 20 different HPV species, including 3 α-HPVs, 16 β-HPVs, and 1 γ-HPV, were detected, 8 of which are reported here for the first time to our knowledge in patients with EV (β-HPV-37, -47, -80, -151, and -159; α-HPV-2 and -57; and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.

SUBMITTER: Saeidian AH

PROVIDER: S-EPMC10077487 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections.

Saeidian Amir Hossein AH Youssefian Leila L Naji Mahtab M Mahmoudi Hamidreza H Barnada Samantha M SM Huang Charles C Naghipoor Karim K Hozhabrpour Amir A Park Jason S JS Manzo Margiotta Flavia F Vahidnezhad Fatemeh F Saffarian Zahra Z Kamyab-Hesari Kambiz K Tolouei Mohammad M Faraji Niloofar N Azimi Seyyede Zeinab SZ Namdari Ghazal G Mansouri Parvin P Casanova Jean-Laurent JL Béziat Vivien V Jouanguy Emmanuelle E Uitto Jouni J Vahidnezhad Hassan H

JCI insight 20230308 5

HPVs are DNA viruses include approximately 450 types that are classified into 5 genera (α-, β-, γ-, μ-, and ν-HPV). The γ- and β-HPVs are present in low copy numbers in healthy individuals; however, in patients with an inborn error of immunity, certain species of β-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either typical or atypical. Manifestations of typical EV are limited to the skin and are caused by abnorm ...[more]

PMID: 36602881

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Project description:Typical epidermodysplasia verruciformis (EV) is a rare, autosomal recessive disorder characterized by an unusual susceptibility to infection with specific skin-trophic types of human papillomavirus, principally betapapillomaviruses, and a propensity for developing malignant skin tumors in sun exposed regions. Its etiology reflects biallelic loss-of-function mutations in TMC6 (EVER1), TMC8 (EVER2) or CIB1. A TMC6-TMC8-CIB1 protein complex in the endoplasmic reticulum is hypothesized to be a restriction factor in keratinocytes for βHPV infection. However, the complex is also present in lymphocytes and its loss may compromise cellular immune control of βHPV infection. Indeed, certain primary immunodeficiencies, iatrogenic immunosuppression and AIDS are associated with the atypical form of EV. While well controlled in immunocompetent mice, murine papillomavirus MmuPV1 was first isolated from immunodeficient mice with florid skin warts, modeling atypical EV. To examine their potential as a model of typical EV, Tmc6-/-, Tmc8-/- or wildtype FVB mice were challenged with MmuPV1. At day 16 post vaginal challenge with MmuPV1, the levels of viral transcripts were similar in Tmc6-/- and Tmc8-/- mice and wildtype FVB mice, arguing against Tmc6/8 acting as intracellular restriction factors. Thereafter, greater clearance of MmuPV1 by the wildtype that the Tmc6-/- and Tmc8-/- FVB mice was evident, supporting the hypothesis that typical EV reflects a subtle cellular immune deficit. Indeed, Tmc6-/- or Tmc8-/- mice exhibit partial CD8 T cell deficits and elevated Treg. While interferon-γ production and surface CD25 were similarly elevated in CD8 T cells upon in vitro stimulation with anti-CD3/CD28, the fraction of Tmc6-/- or Tmc8-/- CD8 T cells that were dividing was lower compared to wildtype. Typical EV patients exhibit normal control of most viral infections; Tmc6-/-, Tmc8-/- and wildtype FVB mice similarly controlled vaccinia virus after skin challenge and induced neutralizing antibodies.

Dataset Information

Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections.

Publications

Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections.

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