Whole transcriptome–based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, β-, and γ-HPV infections
Amir Hossein Saeidian, Leila Youssefian, Mahtab Naji, Hamidreza Mahmoudi, Samantha M. Barnada, Charles Huang, Karim Naghipoor, Amir Hozhabrpour, Jason S. Park, Flavia Manzo Margiotta, Fatemeh Vahidnezhad, Zahra Saffarian, Kambiz Kamyab-Hesari, Mohammad Tolouei, Niloofar Faraji, Seyyede Zeinab Azimi, Ghazal Namdari, Parvin Mansouri, Jean-Laurent Casanova, Vivien Béziat, Emmanuelle Jouanguy, Jouni Uitto, Hassan Vahidnezhad
Amir Hossein Saeidian, Leila Youssefian, Mahtab Naji, Hamidreza Mahmoudi, Samantha M. Barnada, Charles Huang, Karim Naghipoor, Amir Hozhabrpour, Jason S. Park, Flavia Manzo Margiotta, Fatemeh Vahidnezhad, Zahra Saffarian, Kambiz Kamyab-Hesari, Mohammad Tolouei, Niloofar Faraji, Seyyede Zeinab Azimi, Ghazal Namdari, Parvin Mansouri, Jean-Laurent Casanova, Vivien Béziat, Emmanuelle Jouanguy, Jouni Uitto, Hassan Vahidnezhad
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Research Article Dermatology Genetics

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.

Authors

Amir Hossein Saeidian, Leila Youssefian, Mahtab Naji, Hamidreza Mahmoudi, Samantha M. Barnada, Charles Huang, Karim Naghipoor, Amir Hozhabrpour, Jason S. Park, Flavia Manzo Margiotta, Fatemeh Vahidnezhad, Zahra Saffarian, Kambiz Kamyab-Hesari, Mohammad Tolouei, Niloofar Faraji, Seyyede Zeinab Azimi, Ghazal Namdari, Parvin Mansouri, Jean-Laurent Casanova, Vivien Béziat, Emmanuelle Jouanguy, Jouni Uitto, Hassan Vahidnezhad

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Figure 13

Viral repertoire and transcriptomic analysis by gene set enrichment analysis in patients with EV.

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Viral repertoire and transcriptomic analysis by gene set enrichment anal...
(A) Twenty different HPVs were detected in patients with typical EV, using unbiased whole-transcriptome sequencing. A Venn diagram was used to visualize the breakdown of the detected viruses in each group of patients with a mutation in 1 of the 3 typical EV genes, TMC6, TMC8, or CIB1. The predominant HPVs are shown with larger font sizes, previously associated HPVs are shown in blue, and potentially novel associations are shown in red. (B) A PCA plot of the RNA-Seq data characterizes the trends exhibited by the expression profiles of the skin biopsy specimens of healthy control participants, normal-appearing skin of patients with EV, and warts or cancer lesions of patients with EV. Note the distinct expression profile of the 3 examined groups. (C) The volcano plot shows selected DEGs. The log2 fold change indicates the mean expression level for each gene. Each dot represents 1 gene. Black and gray dots represent no significant DEGs between warts and cancer group, and the red dots represent dysregulated genes. (D) The GSEA was used for functional assessment to group genes to sets that share common biological functions and was performed using 1808 DEGs in the wart samples versus cancers. Note the dysregulation of cell cycle–related pathways. Created with BioRender.com. 1000G, 1000 Genomes Project; ExAC, Exome Aggregation Consortium; URR, upstream regulatory region.