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Expanded skin virome in DOCK8-deficient patients

Nature Medicine volume 24, pages 1815–1821 (2018)Cite this article

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Abstract

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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Fig. 1: Skin microbiome of DOCK8-deficient patients is dominated by eukaryotic viruses.
Fig. 2: HPV diversity on skin of DOCK8-deficient patients.
Fig. 3: Longitudinal stability of the skin virome of DOCK8-deficient patients.
Fig. 4: Human RNA viruses in DOCK8-deficient patients and comparison between viral presence in sequencing data and cutaneous lesions.

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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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Acknowledgements

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.

Authors and Affiliations

  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

Authors
  1. Osnat Tirosh
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  2. Sean Conlan
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  3. Clay Deming
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  4. Shih-Queen Lee-Lin
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  5. Xin Huang
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  6. Helen C. Su
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  7. Alexandra F. Freeman
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Consortia

NISC Comparative Sequencing Program

  • 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

Contributions

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.

Corresponding authors

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

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The authors declare no competing interests.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7

Reporting Summary

Supplementary Table 1

DOCK8-deficient patients’ metadata

Supplementary Table 2

Sequencing statistics for all DNA samples

Supplementary Table 3

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

Supplementary Table 4

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

Supplementary Table 5

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

Supplementary Table 6

Polyomavirus relative abundance by sample and by patient

Supplementary Table 7

Herpesviridae relative abundance by sample and by patient

Supplementary Table 8

Anelloviridae relative abundance by sample and by patient

Supplementary Table 9

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

Supplementary Table 10

Novel HPV genomes taxonomy

Supplementary Table 11

Number of human papillomavirus types detected on each patient

Supplementary Table 12

Changes in human papillomavirus communities in longitudinal samplings

Supplementary Table 13

Sequencing statistics for all RNA samples

Supplementary Table 14

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

Supplementary Table 15

Ribosomal RNA reads in all RNA samples

Supplementary Table 16

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

Supplementary Table 17

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

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Tirosh, O., Conlan, S., Deming, C. et al. Expanded skin virome in DOCK8-deficient patients. Nat Med 24, 1815–1821 (2018). https://doi.org/10.1038/s41591-018-0211-7

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