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Illuminating the human virome in health and disease

Authors:
  • Massachusetts General Hospital, Harvard Medical School, Boston USA

Abstract

Abstract Although the microbiome is established as an important regulator of health and disease, the role of viruses that inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still characterizing what constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation. Illuminating this will represent a first step toward developing virome-focused therapies.
C O M M E N T Open Access
Illuminating the human virome in health
and disease
Fatemeh Adiliaghdam
1
and Kate L. Jeffrey
1,2*
Abstract
Although the microbiome is established as an important regulator of health and disease, the role of viruses that
inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still characterizing what
constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward
identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation.
Illuminating this will represent a first step toward developing virome-focused therapies.
Late to the party
In the study of microorganisms, bacteria frequently steal
the limelight. During an influenza outbreak in late 1800,
it was the bacterium Haemophilus influenzae isolated
from sputum that was first presumed to cause disease.
During the 1918 influenza pandemic, urgent efforts to
isolate this causative bacterium failed and it was not
until the 1930s that a filterable agent, a virus, Influenza
H1N1, was identified as the culprit [1]. Similarly, in the
pursuit of understanding human commensal microor-
ganisms, the last 20 years of research has focused almost
exclusively on bacteria and their regulation of our im-
mune and nervous systems. In comparison, very little is
known about eukaryotic and prokaryotic viruses that
also inhabit asymptomatic humans. Given that the name
virus was coined from the Latin word meaning slimy li-
quid or poison and that viruses are considered obligate
pathogens, a possibly beneficial viromeis surprising to
many.
The late start for viruses in the commensal micro-
organism field is in large part due to our inability to
readily culture or detect them, as was the case during
the discovery of the influenza virus. We do not yet know
the eukaryotic cell or bacterial host of most viruses, and
there is no universal 16S ribosomal RNA equivalent, as
in bacteria, allowing for rapid taxonomic
characterization. Technologies such as metagenomics
have only recently enabled identification of viruses in
healthy human tissues. This initially involved sequencing
all DNA or RNA in a sample (human, bacterial, and
viral), and computationally aligning the massive number
of sequences to identify those that resemble known viral
genes. An improvement on this approach now involves
filtering samples to purge eukaryotic cells and bacteria
so that only virus-like particles (VLPs) remain for se-
quencing. However, since the virome consists of both
temperate bacteriophages within bacterial genomes and
free VLPs, both total and VLP sequencing will likely pro-
vide greater representation of all viruses. Nonetheless,
with the approaches taken thus far, studies have revealed
viruses are abundant in human feces, blood, skin, lung,
oral cavity, and an array of other tissues of healthy and
diseased individuals [25].
A moving target
The human intestinal virome established at birth is
dominated by bacteria-infecting viruses, while eukaryotic
viruses gradually emerge after birth [6]. One gram of hu-
man feces contains around 10
8
10
9
VLPs, and explora-
tory sequencing has shown that the identifiable fraction
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* Correspondence: KJeffrey@mgh.harvard.edu
1
Department of Medicine, Division of Gastroenterology and the Center for
the Study of Inflammatory Bowel Disease, Massachusetts General Hospital,
Harvard Medical School, Boston, MA 02114, USA
2
Center for Microbiome Informatics and Therapeutics, Massachusetts Institute
of Technology, Cambridge, MA 02139, USA
Adiliaghdam and Jeffrey Genome Medicine (2020) 12:66
https://doi.org/10.1186/s13073-020-00766-x
of this virome is primarily bacteriophages, including
dsDNA Caudovirales, ssDNA Microviridae [2], and the
recently identified predominant CrAssphage [7]. Viruses
that infect eukaryotic cells within the human fecal vir-
ome have been identified to belong to families Astroviri-
dae,Anelloviridae,Picornaviridae,Caliciviridae, and
Herpesviridae, among others [2,3].
However, many hurdles in our ability to catalog the
human virome remain, making this data far from final.
(1) The vast majority of viruses share little to no hom-
ology with annotated viruses in reference databases. Vi-
ruses infecting animals, plants, fungi, and protozoans
(collectively eukaryotic viruses) number around 100 mil-
lion species while those infecting bacteria are estimated
at 10 trillion, yet a large proportion remain unannotated.
While the NCBI Virus Portal (https://www.ncbi.nlm.nih.
gov/labs/virus/vssi/#/) is reporting new annotations at
an exponential rate, virologists have struggled to distin-
guish clear classes and kingdoms for most of the viro-
sphere, with the exception of a recently published
taxonomic hierarchy [8]. Thus, reanalysis of relatively re-
cent human virome publications may already be war-
ranted. (2) Computational analysis methods vary
considerably across virome studies, as this is a nascent
field, making direct comparisons difficult. (3) Viruses
rely on the host organism for successful replication;
therefore, the discovery of viruses that specifically infect
human cells may be better achieved by analysis of less
accessible tissue and cells, rather than feces or bodily
fluids, where they are likely scarce. (4) False positives in
sequencing data remain an issue as many sequencing re-
agents, or DNA spike-ins during sequencing, are derived
from bacteriophages or bacteria carrying bacteriophages.
A consensus on laboratory techniques and computa-
tional analysis pipelines is a much-needed advance in
the virome field. (5) We still have a very limited perspec-
tive on the healthy human tissue-specific virome. We
know little about the virome in individuals from differ-
ent geographic locations, in those consuming different
diets, and in old or young individuals, and thus, it is dif-
ficult to discern cases of vertical and horizontal trans-
mission or composition changes before, during, and
after disease onset. A tighter grasp on what a healthy vir-
ome looks likean equivalent to the Human Micro-
biome Projectwould allow clearer inferences about
how the virome influences disease.
Making the leap from correlation to causation
Despite the present limitations in characterizing the hu-
man virome in health, robust fluctuations in the virome
in multiple diseases have been reported. In inflammatory
bowel disease (IBD), it was found that enteric Caudovir-
ales temperate phage expanded, although the degree that
this was due to alterations in bacteria remains
unresolved [2,3]. In colorectal cancer, virome signatures
were shown to differentiate individuals at the early ver-
sus late stages of disease. In type I diabetes, expanded
enteric bacteriophage diversity was found to precede dis-
ease and Circoviridae eukaryotic viruses were enriched
in controls. In cystic fibrosis, sputum phage communi-
ties were highly similar and eukaryotic viral communities
were found to be dominated by herpesviruses and retro-
viruses. In graft-versus-host disease (GVHD), a progres-
sive expansion of eukaryotic gut viruses was shown to
follow hematopoietic stem cell transplant, and picobir-
naviruses were associated with early post-transplant
GVHD. In HIV patients, low peripheral CD4 T cell
counts were associated with an expansion of enteric ade-
noviruses [5]. However, this cataloging of diseased vir-
omes is vastly outpacing our mechanistic understanding
as we still do not know whether these altered viromes
actually contribute to disease.
A lesson from the microbiome field, at this juncture
in virome research, would be to move beyond correla-
tions and toward a detailed analysis of how certain vi-
ruses autonomously or cooperatively educate our
physiology. Functional studies in mice have found
that enteric viruses inhabiting a healthy host provide
immune and gut homeostasis. Depletion of viruses or
virus receptors in healthy mice exacerbates intestinal
inflammation while treatment with viral ligands pro-
tects from disease [5]. However, precise mechanisms
by which individual viruses provide protection are
limited. Furthermore, how human virome composition
impacts health or disease remains ambiguous as direct
functional studies are currently lacking. However,
both prokaryotic and eukaryotic viromes possess the
ability to directly immunomodulate their human hosts
based on reports of trans-kingdom interactions of
bacteriophage and human immune cells [9]. Further-
more, given that viruses exist in complex communi-
ties comprising bacteria, fungi, and protozoans,
indirect outcomes of virome changes will almost def-
initely occur through alteration of surrounding micro-
organism communities. Another question and
appealing avenue of investigation is whether com-
mensal viruses impact the hostsabilitytofight
pathogenic viruses through tonic stimulation of anti-
viral immunity or if conversely, acute virus infection
impacts the resident virome. Finally, since complex
disease phenotypes are the result of environmental
triggers in the context of genetic susceptibility, vari-
able impact of the virome will depend on host genet-
ics and should be considered. For instance, a loss-of-
function variant of host virus receptor MDA-5
(encoded by gene IFIH1) associates with incidence of
IBD but protects from type I diabetes [5]suggesting
divergent roles for viruses in different contexts.
Adiliaghdam and Jeffrey Genome Medicine (2020) 12:66 Page 2 of 3
Translating to diagnosis and therapy
The ultimate goal of virome research is to translate find-
ings into diagnostic and therapeutic opportunities. With
accurate mapping of the virome in different human tis-
sues in healthy and disease states, we can begin to use
certain viruses as biomarkers or attempt to manipulate
virome signatures. Moving from association to causation
will confidently enable us to harness the healthy virome
or disrupt the disease-associated one. Uncoupling the
roles of eukaryotic and prokaryotic viruses on immune
state and improvements on propagation of individual
candidate viruses for functional studies will advance
these goals. Therapeutic avenues could also focus on the
beneficial or detrimental host immune responses to vi-
ruses, rather than the viruses themselves to mitigate
virome-related diseases. Viruses may also serve an im-
portant role in fecal microbiota transplants (FMTs) since
filtered feces (removing the bacterial component) have
the same efficacy in treating the Clostridium difficile pa-
tients [10]. However, there is still no knowledge of the
virome composition of FMTs and no consensus on if
this is something we should be measuring in donor and
recipient patients. Finally, benign viruses within the
healthy virome could conceivably be used for safe gene
delivery into humans.
We have just begun to reveal the complexities and
promise of the virome using computational genomics,
but application of the virome remains relatively underex-
plored. Many challenges in the virome field remain, but
let us not repeat history and let bacteria steal the lime-
light. Viruses, fungi, and other commensals within the
human microorganism ecosystem are likely equally im-
portant; we just need to overcome a few more hurdles to
realize their full potential.
Abbreviations
DNA: Deoxyribonucleic acid; RNA: Ribonucleic acid; dsDNA: Double-stranded
DNA; ssDNA: Single-stranded DNA; NCBI: National Center for Biotechnology
Information; HIV: Human immunodeficiency virus; MDA-5: Melanoma
differentiation-associated protein 5
Acknowledgements
The authors would like to thank Hajera Amatullah and Roshan Ahmed for
editorial comments.
Authorscontributions
KLJ conceived and FA and KLJ wrote the manuscript. All authors read and
approved the final manuscript.
Funding
Kenneth Rainin Foundation (Innovator and Synergy Awards to KLJ), NIH
R21AI144877 (KLJ), NIH R01DK119996 (KLJ), Harvard Catalyst | The Harvard
Clinical and Translational Science Center (National Center for Advancing
Translational Sciences, National Institutes of Health Award UL 1TR002541)
and financial contributions from Harvard University and its affiliated
academic healthcare centers (KLJ), MGH Research Scholar, class of 2020 (KLJ).
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 15 July 2020 Accepted: 16 July 2020
References
1. Barry JM. The great influenza: the epic story of the deadliest plague in
history. New York: Penguin Books; 2005. 546 p.
2. Norman JM, et al. Disease-specific alterations in the enteric virome in
inflammatory bowel disease. Cell. 2015;160(3):44760.
3. Clooney AG, et al. Whole-virome analysis sheds light on viral dark matter in
inflammatory bowel disease. Cell Host Microbe. 2019;26(6):76478.e5.
4. Schmidt C. The virome hunters. Nat Biotechnol. 2018;36(10):9169.
5. Neil JA, Cadwell K. The intestinal virome and immunity. J Immunol. 2018;
201(6):161524.
6. Liang G, et al. The stepwise assembly of the neonatal virome is modulated
by breastfeeding. Nature. 2020;581(7809):4704.
7. Dutilh BE, et al. A highly abundant bacteriophage discovered in the
unknown sequences of human faecal metagenomes. Nat Commun. 2014;5:
4498.
8. International Committee on Taxonomy of Viruses Executive, C. The new
scope of virus taxonomy: partitioning the virosphere into 15 hierarchical
ranks. Nat Microbiol. 2020;5(5):66874.
9. Sweere JM, et al. Bacteriophage trigger antiviral immunity and prevent
clearance of bacterial infection. Science. 2019;363(6434):eaat9691.
10. Ott SJ, et al. Efficacy of sterile fecal filtrate transfer for treating patients with
Clostridium difficile infection. Gastroenterology. 2017;152(4):799811 e7.
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Adiliaghdam and Jeffrey Genome Medicine (2020) 12:66 Page 3 of 3
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The human gut virome is thought to significantly impact the microbiome and human health. However, most virome analyses have been performed on a limited fraction of known viruses. Using whole-virome analysis on a published keystone inflammatory bowel disease (IBD) cohort and an in-house ulcerative colitis dataset, we shed light on the composition of the human gut virome in IBD beyond this identifiable minority. We observe IBD-specific changes to the virome and increased numbers of temperate phage sequences in individuals with Crohn's disease. Unlike prior database-dependent methods, no changes in viral richness were observed. Among IBD subjects, the changes in virome composition reflected alterations in bacterial composition. Furthermore, incorporating both bacteriome and virome composition offered greater classification power between health and disease. This approach to analyzing whole virome across cohorts highlights significant IBD signals, which may be crucial for developing future biomarkers and therapeutics.
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Ambitious efforts to catalog viruses across the globe may facilitate our understanding of viral communities and ecology, boost infectious disease diagnostics and surveillance, and spur new therapeutics. Charles Schmidt investigates.
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The composition of the human microbiome is considered a major source of interindividual variation in immunity and, by extension, susceptibility to diseases. Intestinal bacteria have been the major focus of research. However, diverse communities of viruses that infect microbes and the animal host cohabitate the gastrointestinal tract and collectively constitute the gut virome. Although viruses are typically investigated as pathogens, recent studies highlight a relationship between the host and animal viruses in the gut that is more akin to host-microbiome interactions and includes both beneficial and detrimental outcomes for the host. These viruses are likely sources of immune variation, both locally and extraintestinally. In this review, we describe the components of the gut virome, in particular mammalian viruses, and their ability to modulate host responses during homeostasis and disease.
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Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.