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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Data availability

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.

Author information

Author notes

  1. These authors contributed equally: Julia A. Segre and Heidi H. Kong.

  2. A full list of members and their affiliations appears at the end of the paper.


  1. Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA

    • Osnat Tirosh
    • , Sean Conlan
    • , Clay Deming
    • , Shih-Queen Lee-Lin
    • , Xin Huang
    •  & Julia A. Segre
  2. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA

    • Helen C. Su
    •  & Alexandra F. Freeman
  3. Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    • Heidi H. Kong
  4. Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA

    • Heidi H. Kong
  5. NIH Intramural Sequencing Center, National Human Genome Research Institute, Bethesda, MD, USA

    • Beatrice B. Barnabas
    • , Gerard G. Bouffard
    • , Shelise Y. Brooks
    • , Holly Marfani
    • , Lyudmila Dekhtyar
    • , Xiaobin Guan
    • , Joel Han
    • , Shi-ling Ho
    • , Richelle Legaspi
    • , Quino L. Maduro
    • , Catherine A. Masiello
    • , Jennifer C. McDowell
    • , Casandra Montemayor
    • , James C. Mullikin
    • , Morgan Park
    • , Nancy L. Riebow
    • , Karen Schandler
    • , Chanthra Scharer
    • , Brian Schmidt
    • , Christina Sison
    • , Sirintorn Stantripop
    • , James W. Thomas
    • , Pamela J. Thomas
    • , Meghana Vemulapalli
    •  & Alice C. Young


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  1. NISC Comparative Sequencing Program


O.T., S.C., H.C.S., A.F.F., J.A.S., and H.H.K. contributed to the design and conception of the study. Sequencing was carried out by NISC. O.T., S.C., C.D., S.-Q.L.-L., and X.H. performed the experiments and analyses. O.T., J.A.S., and H.H.K. drafted the manuscript. All authors revised the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Julia A. Segre or Heidi H. Kong.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–7

  2. Reporting Summary

  3. Supplementary Table 1

    DOCK8-deficient patients’ metadata

  4. Supplementary Table 2

    Sequencing statistics for all DNA samples

  5. Supplementary Table 3

    Kingdom-level relative abundance by sample of healthy adults and children

  6. Supplementary Table 4

    Kingdom-level relative abundance by sample of DOCK8-deficient patients

  7. Supplementary Table 5

    Viral family taxonomic classifications of all DOCK8-deficient patients’ skin

  8. Supplementary Table 6

    Polyomavirus relative abundance by sample and by patient

  9. Supplementary Table 7

    Herpesviridae relative abundance by sample and by patient

  10. Supplementary Table 8

    Anelloviridae relative abundance by sample and by patient

  11. Supplementary Table 9

    Percent and number of DNA reads mapped to each of the reference databases and novel HPV genomes

  12. Supplementary Table 10

    Novel HPV genomes taxonomy

  13. Supplementary Table 11

    Number of human papillomavirus types detected on each patient

  14. Supplementary Table 12

    Changes in human papillomavirus communities in longitudinal samplings

  15. Supplementary Table 13

    Sequencing statistics for all RNA samples

  16. Supplementary Table 14

    Viral family-level relative abundance by sample from RNA sequencing data

  17. Supplementary Table 15

    Ribosomal RNA reads in all RNA samples

  18. Supplementary Table 16

    Assembly statistics for de novo assembly of DNA data by metaSpades, individual samples

  19. Supplementary Table 17

    Assembly statistics for de novo assembly of RNA data by rnaSpades, individual samples

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