A tissue level atlas of the healthy human virome

Abstract

Background: Human-resident microbes can influence both health and disease. Investigating the microbiome using next-generation sequencing technology has revealed examples of mutualism and conflict between microbes and humans. Comparing to bacteria, the viral component of the microbiome (i.e., the "virome") is understudied. Somatic tissues of healthy individuals are usually inaccessible for the virome sampling; therefore, there is limited understanding of the presence and distribution of viruses in tissues in healthy individuals and how virus infection associates with human gene expression and perturbs immunological homeostasis. Results: To characterize the human virome in a tissue-specific manner, here we performed meta-transcriptomic analysis using the RNA-sequencing dataset from the Genotype-Tissue Expression (GTEx) Project. We analyzed the 8991 RNA-sequencing data obtained from 51 somatic tissues from 547 individuals and successfully detected 39 viral species in at least one tissue. We then investigated associations between virus infection and human gene expression and human disease onset. We detected some expected relationships; for instance, hepatitis C virus infection in the liver was strongly associated with interferon-stimulated gene upregulation and pathological findings of chronic hepatitis. The presence of herpes simplex virus type 1 in one subject's brain strongly associated with immune gene expression. While torque teno virus was detected in a broad range of human tissues, it was not associated with interferon responses. Being notable in light of its association with lymphoproliferative disorders, Epstein-Barr virus infection in the spleen and blood was associated with an increase in plasma cells in healthy subjects. Human herpesvirus 7 was often detected in the stomach; intriguingly, it associated with the proportion of human leukocytes in the stomach as well as digestive gene expression. Moreover, virus infections in the local tissues associated with systemic immune responses in circulating blood. Conclusions: To our knowledge, this study is the first comprehensive investigation of the human virome in a variety of tissues in healthy individuals through meta-transcriptomic analysis. Further investigation of the associations described here, and application of this analytical pipeline to additional datasets, will be useful to reveal the impact of viral infections on human health.

Omission of non-poly(A) viral transcripts from the tissue level atlas of the healthy human virome

“…In this regard, some RNA viruses (e.g., Flaviviruses) potentially produce nonpoly(A) RNAs. Therefore, in terms of the description of the human virome, particularly that of human RNA viruses, we cannot exclude the possibility that the results shown in our recent paper [10] are incomplete. If there were large datasets available that included the data of non-poly(A) RNAs, it would be possible to survey the bona fide human virome more efficiently and effectively, as suggested by Altmäe et al…”

“…In short, the recently presented tissue level atlas of the healthy human virome should be acknowledged as a partial tissue level atlas, and the comprehensive investigation should be completed with meta-transcriptome analysis of data generated using the total RNA extraction method in order to achieve a more complete view of the human virome. In our recent paper in BMC Biology titled "A tissue level atlas of the healthy human virome" [10], we performed meta-transcriptomic analysis using the RNA-sequencing (RNA-Seq) dataset from the Genotype-Tissue Expression (GTEx) Project, which includes 8991 RNA-Seq data obtained from 51 somatic tissues from 547 individuals. In this study, we detected 39 viral speciesOmission of non-poly(A) viral transcripts from the tissue in at least one tissue and furthermore investigated associations between virus infection (e.g., hepatitis C virus and some human herpes viruses) and human gene expression [e.g., type I interferons (IFNs) and IFN-stimulated genes].…”

“…As described in the first sentence of the "Method" section of our paper [10], we used the pair-ended, poly(A)- Fig. 1 .…”

CLCA4 and MS4A12 as the significant gene biomarkers of primary colorectal cancer

“…One online tool, DAVID ( https://david.ncifcrf.gov/home.jsp ) (version 6.8, Maryland, America), was applied to carried out the functional annotation for DEGs. Gene Ontology (GO) [ 26 ] generally perform enrichment analysis of genomes. And there are mainly cellular components (CC), biological processes (BP), and molecular functions (MF) in the GO analysis.…”

Virus-derived variation in diverse human genomes

“…We detected reads mapping to 634 viruses, including 553 phages, in total (Supplemental figure 1 (the original heat map, showing all viruses by all people)). Phage are ubiquitous in the human virome and thus should not necessarily be excluded as a potential source of horizontal gene flow to humans (56). Phage-mapped reads were often found, however they were present at low depth inconsistent with germline integration into human genomes, and were thus excluded from further analysis.…”