Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1,2,3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial–host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.
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The sequencing data and genome assemblies for this study are linked to the NCBI BioProject ID PRJNA471898.
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This study utilized the high-performance computational capabilities of the NIH Biowulf Linux cluster (http://hpc.nih.gov). We thank M. Park, P. Thomas, A. Young, S. Phang, A. Pradhan, V. Pillai, J. Fekecs, NIH Patient Photography, and W.-I. Ng for underlying efforts, and the Segre and Kong laboratories for helpful discussions. We appreciate the participation of patients and their families. This work was supported by the National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Programs.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–7
DOCK8-deficient patients’ metadata
Sequencing statistics for all DNA samples
Kingdom-level relative abundance by sample of healthy adults and children
Kingdom-level relative abundance by sample of DOCK8-deficient patients
Viral family taxonomic classifications of all DOCK8-deficient patients’ skin
Polyomavirus relative abundance by sample and by patient
Herpesviridae relative abundance by sample and by patient
Anelloviridae relative abundance by sample and by patient
Percent and number of DNA reads mapped to each of the reference databases and novel HPV genomes
Novel HPV genomes taxonomy
Number of human papillomavirus types detected on each patient
Changes in human papillomavirus communities in longitudinal samplings
Sequencing statistics for all RNA samples
Viral family-level relative abundance by sample from RNA sequencing data
Ribosomal RNA reads in all RNA samples
Assembly statistics for de novo assembly of DNA data by metaSpades, individual samples
Assembly statistics for de novo assembly of RNA data by rnaSpades, individual samples
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