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The Intestinal Virome and Immunity Jessica A. Neil and Ken Cadwell J Immunol 2018; 201:1615-1624; ; This information is current as doi: 10.4049/jimmunol.1800631 of September 27, 2021. http://www.jimmunol.org/content/201/6/1615 Downloaded from References This article cites 130 articles, 42 of which you can access for free at: http://www.jimmunol.org/content/201/6/1615.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Intestinal Virome and Immunity Jessica A. Neil and Ken Cadwell The composition of the human microbiome is considered to the detriment or benefit of the host, much like the bacterial a major source of interindividual variation in immunity microbiome. and, by extension, susceptibility to diseases. Intestinal Although the study of virology has generally focused on bacteria have been the major focus of research. How- disease-causing animal viruses, a large fraction of the virome is ever, diverse communities of viruses that infect microbes composed of bacteriophages and endogenous retroviral ele- ments. Approximately 1015 bacteriophages exist in the human and the animal host cohabitate the gastrointestinal tract 8 9 and collectively constitute the gut virome. Although intestine (5). A gram of human stool contains 10 –10 virus- viruses are typically investigated as pathogens, recent like particles (6). The majority of these contain a DNA genome. Among the DNA viruses that can be matched studies highlight a relationship between the host and to an annotated genome, 99% are bacteriophages and the Downloaded from animal viruses in the gut that is more akin to host– remaining 1% are animal viruses such as anellovirus, parvo- microbiome interactions and includes both beneficial virus, adenovirus, and papillomavirus (6). Intrapersonal bac- and detrimental outcomes for the host. These viruses teriophage abundance is mostly stable over time but does are likely sources of immune variation, both locally show rapid sequence diversification (7). The predominant and extraintestinally. In this review, we describe the classifiable bacteriophage species in the gut are the dsDNA components of the gut virome, in particular mamma- Caudovirales and ssDNA Microviridae (8). However, one http://www.jimmunol.org/ lian viruses, and their ability to modulate host responses uncharacterized dsDNA bacteriophage known as crAssphage during homeostasis and disease. The Journal of Immu- is present in 73% of fecal metagenomes and predicted to nology, 2018, 201: 1615–1624. infect Bacteroides species that are prevalent in the human gut (9, 10). In addition to directly influencing microbiome population dynamics by killing their bacterial hosts during he human body harbors diverse populations of in- lytic release of viral particles, bacteriophages that integrate fectious entities, collectively known as the micro- into bacterial genomes contribute to the coding potential of biome, which interact with each other and with the the microbiome to indirectly influence the physiology of the T by guest on September 27, 2021 host to influence health and disease. Although the most animal host (8). commonly studied are the bacterial members of the micro- Endogenous retroviruses (ERVs) resemble present-day exog- biome, there are vast numbers of viruses present in the human enous retroviruses but are integrated in the host genome and body. Together, these viruses form the virome. Comprehen- transferred vertically between generations. They are estimated sive annotation of the human virome is confounded by the to make up 8% of the human genome (11). The syncytin staggering diversity of viruses detected at multiple anatomical proteins that mediate placental development are derived from sites that can have ssRNA, dsRNA, ssDNA, or dsDNA ge- ERV env genes, and ERVs have dispersed IFN-inducible nomes. Despite this challenge, recent advances in sequencing enhancer elements throughout mammalian genomes, suggesting and analysis of metagenomic data have facilitated the dis- that retroviral integration played a substantial role in mammalian covery of new viruses and improved our ability to catalog viral evolution (12). Although most ERVs have accumulated many communities in an unbiased manner (1, 2). These pioneering changes to their sequence over time that have rendered them efforts reveal substantial intestinal virome diversity between defective, there are a limited number of ERVs with the potential individuals likely due to differences in bacterial composition to produce viral products that activate immune response or and diet (3, 4). Studies comparing the virome between indi- promote tumorigenesis (12–15). ERVs can also facilitate in- viduals have contributed to the growing evidence that dif- sertional mutagenesis and chromosomal rearrangements that ferential exposure to viruses influences host physiology, either affect cellular gene expression (16). The virome can also include Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Address correspondence and reprint requests to Dr. Ken Cadwell, New York University Institute of Biomolecular Medicine, New York University School of Medicine, New School of Medicine, Alexandria Center for Life Sciences-West Tower 409, 430 East 29th York, NY 10016; and Department of Microbiology, New York University School of Street, New York, NY 10016. E-mail address: [email protected] Medicine, New York, NY 10016 Abbreviations used in this article: CVB, coxsackievirus B; DC, dendritic cell; DSS, ORCIDs: 0000-0003-2824-3701 (J.A.N.); 0000-0002-5860-0661 (K.C.). dextran sodium sulfate; ERV, endogenous retrovirus; FMT, fecal microbiome transplan- tation; GVHD, graft-versus-host disease; gHV-68, gammaherpesvirus 68; IBD, inflam- Received for publication May 2, 2018. Accepted for publication May 21, 2018. matory bowel disease; IFN-I, type I IFN; ILC3, group 3 innate lymphoid cell; IRF1, This work was supported by National Institutes of Health Grants HL123340, IFN regulatory factor 1; MDA5, melanoma differentiation–associated protein 5; MNV, DK093668, DK103788, and AI121244, a Faculty Scholar grant from the Howard murine norovirus; NLR, Nod-like receptor; PRR, pattern recognition receptor; RIG-I, Hughes Medical Institute, the Stony Wold–Herbert Fund, the Merieux Institute, retinoic acid inducible gene I; T1D, type 1 diabetes; VRE, vancomycin-resistant the Rainin Foundation, a Burroughs Wellcome Fund Investigator in the Pathogenesis Enterococcus. of Infectious Diseases award (to K.C.), a Sir Keith Murdoch Fellowship, and a Vilcek Fellowship (to J.A.N.). Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800631 1616 BRIEF REVIEWS: VIRAL COMPONENTS OF THE MICROBIOME plant viruses, likely introduced through food, and viruses that unlikely to be silent passengers. Recent studies highlight how infect archaea and eukaryotic members of the microbiome such the gastrointestinal tract is an important site for virus–micro- as fungi (mycobiome). One study showed that 97% of virus-like biome and virus–host interactions that likely contribute to particles from the healthy human gut that harbor an RNA interindividual variation in immunity and disease susceptibility genome represent pathogenic plant viruses, with the remaining (Fig. 1). Therefore, in this article, we will focus on the impact 3% belonging to animal viruses (17). How these viruses affect of intestinal animal viruses as modifiers of the immune system. animal hosts is unknown. We will first review the pathways involved in recognition and The remainder of the virome consists of RNA and DNA responding to intestinal infection and provide evidence of animal viruses that are not integrated into the germ line. At any functional interactions between animal viruses and the bac- given time, an individual human harbors multiple animal terial microbiome. We will next discuss the beneficial and viruses, many of which establish chronic infections (18–20). detrimental impact of intestinal infections by viruses beyond The prevalence of animal viruses that cause transient infec- their role as pathogens. At the end, we use examples of tions, also considered part of the virome, can be more difficult how knowledge gained from the study of viral infections at to investigate, especially if the infection is asymptomatic. In nonintestinal sites can guide future research into the gut contrast to serological methods that capture the infectious virome. history of an individual (21), metagenomic studies may miss the contribution of a virus that is no longer present in a Immune responses to enteric viruses patient or diseased tissue. Additionally, chronic infections