Unmasking the Tissue-Resident Eukaryotic DNA Virome in Humans

Abstract Background Little is known on the landscape of viruses that have taken residence within our cells, nor on the interplay with the host imperative for their persistence. Yet, a lifetime of interactions conceivably have an imprint on our physiology and immune phenotype. Importantly, current metagenomics-insights on the healthy human virome are derived from bodily fluids, which are only a proxy of the true prevalence of human eukaryotic viruses within tissues. Most significantly, the virome’s systemic composition in an individual has thus far remained uncharted. Results In this work, we revealed the genetic make-up of the eukaryotic human DNA virome in the body and showed that each organ (colon, liver, lung, heart, brain, kidney, skin, blood, hair) has unique viral compositions. By integration of quantitative (qPCR) and qualitative (hybrid-capture sequencing) analysis, we identified the DNAs of 17 viruses, primarily herpes-, parvo-, papilloma- and anello-viruses (>80% prevalence), typically persisting in low copies (mean 540 copies/ million cells). The within-sample diversities (a-diversity) were highest in the lung, liver, colon, and kidney. We assembled in total 70 viral genomes (>90% breadth coverage), distinct in each of the individuals, and identified high sequence homology across the organs. Moreover, we detected variations in virome composition and distribution in two individuals with underlying malignant conditions. Conclusions Our findings reveal unprecedented prevalences of viral DNAs in human organs. We showed that bodily fluids, although accessible to sampling, fail to deliver a comprehensive view of the numerous intracellular viruses colonizing our tissues. Our data demonstrate how a multi-organ approach is essential for analyzing differing virome compositions in various disease states. This atlas provides a fundamental ground for the studies of correlates to disease, and for the interpretation of next-generation sequencing data in clinical virology. Ultimately, our findings call for investigation of the crosstalk between human DNA viruses, the host, and other microbes, as it predictably has a significant impact on our health.