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The Intestinal 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 October 1, 2021. http://www.jimmunol.org/content/201/6/1615

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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 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 has generally focused on have been the major focus of research. How- disease-causing , a large fraction of the virome is ever, diverse communities of viruses that infect microbes composed of 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 - viruses are typically investigated as pathogens, recent like particles (6). The majority of these contain a DNA . 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 species in the gut are the dsDNA components of the gut virome, in particular mamma- and ssDNA (8). However, one lian viruses, and their ability to modulate host responses uncharacterized dsDNA bacteriophage known as crAssphage http://www.jimmunol.org/ 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 contribute to the coding potential of T biome, which interact with each other and with the the microbiome to indirectly influence the physiology of the host to influence health and disease. Although the most animal host (8). by guest on October 1, 2021 commonly studied are the bacterial members of the micro- Endogenous (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 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 (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 Sciences-West Tower 409, 430 East 29th York, NY 10016; and Department of , 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, B; DC, dendritic cell; DSS, ORCIDs: 0000-0003-2824-3701 (J.A.N.); 0000-0002-5860-0661 (K.C.). dextran sodium sulfate; ERV, endogenous ; 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 ; 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 viruses, likely introduced through food, and viruses that unlikely to be silent passengers. Recent studies highlight how infect 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 . 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 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 (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 are Unlike bacteria, viruses need to infect host cells within the often difficult to detect because certain viruses can exist in a gastrointestinal tract to support their propagation. Target cells Downloaded from quiescent state (latency), and the immune system may restrict include the one-layer thick epithelial cells that serve the dual replication to levels that are undetectable by conventional function of facilitating nutrient exchange and a physical barrier methods. In one of the few longitudinal virome studies against invasion (23). Dendritic cells (DCs) and macrophages performed to date, fecal samples from healthy human infants within the lamina propria (tissue underlying the epithelium) were shown to harbor RNA and DNA animal viruses be- and GALT (such as Peyer patches) also commonly encounter longing to 16 distinct families during the first 24 mo of life viruses (24). Nucleic acid derived from enteric viruses are http://www.jimmunol.org/ (22). By adulthood, a typical individual will have been in- sensed by these cells through many of the same pattern rec- fected by at least 10 different viruses, with some individuals ognition receptors (PRRs) that are important at other sites. showing evidence of infection by 50–100 viral species (21). These include endosomal TLRs that signal through MYD88 The traditional paradigm of host–pathogen interactions, in and TRIF and the cytosolic sensors retinoic acid inducible which infection by an individual agent directly produces gene I (RIG-I) and melanoma differentiation–associated immediate disease, fails to fully capture our relationship with protein 5 (MDA5) that signal through MAVS to stimulate the many of these animal viruses. The necessity of the host expression of type I IFN (IFN-I) and type III IFN (IFN-III) machinery for their life cycle suggests that these viruses are (24). Both RIG-I and MDA5 are necessary for optimal antiviral by guest on October 1, 2021

FIGURE 1. Virus–microbiome and virus–host genome interactions in immune variation. The host microbiome is a complex network of viruses, bacteria, and other or- ganisms (fungi, archaea, protozoans, and helminths) that reside in the human body. The virome is composed of animal viruses, bacteriophages, and ERVs. The gastro- intestinal tract is inhabited by vast numbers of viruses and is an important site for virus–microbiome inter- actions and virus–host genome interactions. Intestinal bacteria interact with the virome by harboring bacte- riophages and facilitating infection of barrier cells by animal viruses. Although typically investigated as path- ogens, this review highlights how animal viruses in the gut serve as immune modulators that potentially explain interindividual differences in disease susceptibility. The responses induced by various virus–microbiome and vi- rus–host genome interactions likely alter the magnitude and function of the immune response to either the det- riment or benefit of the host leading to either potentia- tion or protection from disease. The Journal of Immunology 1617 responses to , a dsRNA virus that infects the small in- persistent norovirus infection may be contributing to mor- testinal epithelium to cause diarrheal disease in children (25). bidity in immunocompromised individuals or facilitating Sensing of ssRNA , which also cause (47, 48). Remarkably, administration of rIFN-l in , can occur through MDA5, TLR7, and TLR3 in is sufficient to clear infection of a persistent strain of MNV myeloid cells (26, 27). Although best known for responding to independently of the adaptive immune response (29, 49). As bacteria, recent studies suggest that cytosolic Nod-like receptors we discuss throughout this article, the induction of IFNs is a (NLRs) have an intestine-specific role in restricting viruses. Mice hallmark of viral infection and likely mediates many of the deficient in NLRP6, which can serve as a cofactor for RNA consequences of enteric viruses on host physiology. helicase DHX15 to signal through MAVS, display a blunted IFN-I/III response and are susceptible to oral infection by en- Impact of bacteria on enteric virus infection cephalomyocarditis virus and murine norovirus (MNV) (28). Depletion of intestinal bacteria often reduces the replication The multiple pathways involved in norovirus recognition may of enteric viruses, as the bacterial microbiome is known to reflect interstrain differences or their ability to infect broad cell facilitate viral infection and modify antiviral immune responses types, including myeloid cells, lymphocytes, and the specialized (50, 51). Optimal infectivity is dependent on the sensory epithelial cells known as tuft cells (29–32). Inhibiting stabilization of virions upon binding to bacterial surface the ability of MNV to engage these rare tuft cells prevents in- polysaccharides (52, 53). Binding to bacteria also promotes fection, highlighting the importance of an exquisitely specific poliovirus attachment to target cells, which can enhance viral cell tropism and remarkable adaptation of enteric viruses (30). fitness by facilitating with multiple virions and Downloaded from Rotavirus RNA is sensed by NLRP9b and another RNA genetic recombination events between viral strains (54). For helicase DHX9 in the intestinal epithelium and is essential for similar reasons, intestinal titers and signs of inflammation are 2 2 inflammasome-mediated cell death (pyroptosis). Given that reduced following infection of antibiotic-treated Ifnar1 / antagonize IFN signaling, this pathway may explain mice with reovirus (52). During vertical transmission of mouse why other PRRs are inadequate for controlling this virus (33). mammary tumor virus through maternal milk, LPS bound Despite the ability of certain viruses to evade IFN responses, to virions from the mother stimulates the production of the http://www.jimmunol.org/ numerous studies highlight the essential role of these cytokines immunosuppressive cytokine IL-10 in the pups to allow the during intestinal infection. IFN-I (IFN-a and IFN-b) binds establishment of infection (55). Treatment of mice with the IFN-a/b receptor (IFNAR1 and IFNAR2 complex), antibiotics also decreases intestinal MNV replication (32, whereas IFN-III (IFN-l) binds the IFN-l receptor (IFNLR1 56, 57). Here, bacteria reduce the efficacy of IFN-l–mediated and IL-10R2 complex) to induce an antiviral gene expression viral clearance and enhance infection of B cells (32, 56). During program. Although the exact effector mechanisms in the gut rotavirus infection, bacteria reduce systemic and intesti- remain obscure, they are presumably similar to other sites of nal anti-rotavirus IgA titers to support increased rotavirus infection and involve IFN-stimulated genes (ISGs) that reduce replication (58). These studies indicate that animal viruses (e.g., modification of viral RNA) and induce that infect the gastrointestinal tract have adapted to the presence by guest on October 1, 2021 a refractory state in neighboring uninfected cells. IFNAR1 is of bacteria. broadly expressed on a variety of cell types and is necessary for preventing systemic dissemination of MNV, rotavirus, and Beneficial impact of viruses in the gut reovirus (34). In contrast, the relatively restricted expression of The importance of the microbiome to the intestinal envi- IFNLR1 to epithelial cells suggests it has a more defined role ronment is apparent in germ-free mice, which display nu- in controlling mucosal viral replication (35). IFN-l, in com- merous intestinal and immune abnormalities due to the lack of bination with IL-22 production by group 3 innate lymphoid microbial communities (59). Germ-free mice and mice treated cells (ILC3s), effectively controls intestinal rotavirus infection with antibiotics also show increased susceptibility to models (36). IFN-l signaling in epithelial cells is also required to of intestinal damage, peanut allergy, allergic asthma, and regulate fecal shedding and viral replication in mice infected bacterial infections (60–64). Although in some cases intestinal with MNV and reovirus (37). IFNs also promote adaptive bacteria are sufficient to modulate these responses, in many immune responses (38), which are critical for control of en- models a role for the virome cannot be ruled out, especially teric viruses (39–42). Suboptimal CD8+ T cell responses given that antiviral signaling has a prominent role in diseases and avoidance of CD8+ T cell detection are associated with involving the gut. Nonhematopoietic expression of MAVS is MNV persistence (43, 44). Furthermore, successful vaccination required to protect mice against colitis following intestinal against rotavirus directly correlates with IgA production (45). injury by dextran sodium sulfate (DSS) (65). Similarly, IFN-I Although we emphasize the role of cytokines downstream of signaling following stimulation of the MAVS and RIG-I PRRs in subsequent sections as a common means by which pathways improves intestinal barrier function and protects viruses affect host physiology, understanding how adaptive mice from graft-versus-host disease (GVHD), a complica- immunity functions or fails to control enteric viruses remains tion that occurs following allogeneic stem cell transplan- an important topic with direct relevance to vaccine efforts. tation (66). In another example, administration of a TLR7 Boosting innate immunity may be an effective strategy agonist enhances colonization resistance to vancomycin- for overcoming insufficient antiviral immunity in the gut. resistant Enterococcus (VRE), a common hospital-acquired Treatment with bacterially derived flagellin prevents and cures opportunistic pathogen, by stimulating DCs that induce chronic rotavirus infection of mice by triggering IL-22 and IL-22 production by ILC3s (27). Another example in which IL-18 production through TLR5 and NLRC4, respec- intestinal viruses potentially promote colonization resistance tively (46). For noroviruses, effective antivirals and vaccines was observed during fecal microbiome transplantation (FMT) currently do not exist, and there is increased concern that in patients harboring Clostridium difficile. Surprisingly, filtrated 1618 BRIEF REVIEWS: VIRAL COMPONENTS OF THE MICROBIOME feces (to remove the bacterial component and retain viruses) It is possible that these effects extend beyond the gastrointes- have the same efficacy as nonfiltrated feces in treating the pa- tinal tract because MNV infection protects mice from lung tients (67). It is possible that the active component of the FMT injury following infection with Pseudomonas aeruginosa (69), consists of bacteriophages because patients with C. difficile in- and MNV restores serum Ig in germ-free mice to levels fection had altered bacteriophage abundance and richness observed in conventional mice (57). The observation that compared with healthy controls,andsuccessfultransplan- norovirus RNA is detected in up to 16% of healthy humans tation was associated with transfer of Caudovirales species reinforces the need to understand how enteric viral infections (68). These and other observations indirectly suggest that impact host biology when they are not causing diarrheal disease enteric viral infections fortify the intestinal barrier in certain (70). situations via triggering beneficial immune responses or Other animal viruses may also promote intestinal homeostasis. influencing the bacterial microbiome. Treatment of mice with a mixture of antivirals increases the Mechanistic experiments in mice, especially with MNV severity of DSS-induced colitis, whereas treatment with inacti- infections, provide formal evidence that viruses can function vated rotavirus or TLR3/7 agonists reduces disease (71). In this as a subset of the microbiome in a manner analogous to case, the protective effect of TLR ligation was attributed to intestinal bacteria (Table I). Many MNV strains establish IFN-I expression by plasmacytoid DCs. This response to viruses persistent infection in the intestine, frequently in the absence may be conserved in humans because TLR3 and TLR7 gene of obvious symptoms. Infection by a persistent strain of variants are associated with increased severity of inflammatory MNV compensates for the absence of bacteria in germ-free bowel disease (IBD) in patients (71). Murine CMV, a herpes- mice by restoring intestinal morphology and promoting virus that chronically infects a variety of tissues and cell types, Downloaded from lymphocyte differentiation (57). In addition, MNV protects promotes turnover of the epithelium in multiple organs in- antibiotic-treated mice from DSS-induced intestinal injury in a cluding the intestine. This effect was attributed to epithelial manner dependent on IFNAR1 (57). MNV can also protect proliferation induced by the ISG Apol9a/b expressed by mac- antibiotic-treated mice from inflammatory lesions during rophages downstream of elevated IFN-I and was shown to superinfection with the intestinal bacterial pathogen Citrobacter enhance intestinal wound healing (72). When taken together, rodentium and reduces colonization by VRE (27, 57). The these studies show that IFN-I and other antiviral responses http://www.jimmunol.org/ recent discovery that MNV infects tuft cells, which coordinate induce factors that promote intestinal epithelial health in ad- type 2 immune responses and mucus production, suggests that dition to those that inhibit viral replication. Whether IFNs in infection by this virus could directly influence the function of the gut are beneficial to the host may be context-specific and the intestinal epithelium and warrants further investigation (30). not without controversy (24). A major future direction is to

Table I. Examples in which intestinal viruses contribute to protection against or potentiation of diseases by guest on October 1, 2021

Virus Model Outcome Mechanism Reference MNV Germ-free and broad- Restoration of intestinal Dependent on IFN-I (57) spectrum antibiotic- architecture, immune cell treated wild type mice populations, and resistance to chemically induced colitis Ampicillin-treated Colonization resistance Increased IL-22+ ILC3 (27) wild type mice to VRE Atg16L1 mutant mice Crohn disease–like lesions Paneth cell necroptosis due (80) in the small intestine to virally induced TNF-a (81) 2 2 IL-10 / mice Intestinal inflammation Dependent on bacteria (83) H. bilis–infected Intestinal inflammation Unknown (82) 2 2 MDR1a / mice Wild type mice Protection from lung Unknown (69) damage following P. aeruginosa infection Reovirus DQ8 transgenic mice Celiac disease manifestations Suppression of peripheral (76) and humans regulatory T cells and promotion of IRF1 and Th1 immunity to dietary Ag Caudovirales bacteriophage Humans Crohn disease Virus–microbiome (86) interaction Successful treatment of Transfer of species from (68) C. difficile by FMT healthy donors Picobirnaviridae Humans Severe enteric GVHD Unknown (88) CVB NOD mice Accelerated autoimmune Virus spread to the pancreas (91) diabetes onset and local IFN-I response Rotavirus NOD mice Accelerated autoimmune IFN-I–dependent bystander (96) diabetes onset activation of lymphocytes in (97) the pancreatic lymph nodes Humans Protection from T1D Unknown (101) Adenovirus and anellovirus Human HIV disease progression Unknown (104) Animal models and observations in patients provide evidence for a role of intestinal viruses in modulating susceptibility to a range of disease conditions, including intestinal inflammation (IBDs, celiac disease, and opportunistic colonization by antibiotic-resistant bacteria) and extraintestinal disorders (T1D, lung infections, and HIV). Mechanisms frequently involve cytokines produced in response to viral infection that act on surrounding tissue or induce the mobilization of lymphoid cells. The outcome can be beneficial or detrimental to the host depending on whether a heightened state of immunity is desirable (e.g., protection against an infection versus fueling a chronic inflammatory disease). The Journal of Immunology 1619 elucidate the specific mechanisms of action downstream of bacteriophage expansion was associated with decreased bac- IFN signaling in the models described above. terial diversity suggesting that virus–microbiome interactions contribute to disease pathogenesis (86). A similar expansion of Negative impact of viruses in the gut bacteriophage diversity is observed in patients with colorectal Excess IFN-I production and other antiviral responses in the cancer, and specific bacteriophage signatures can delineate pa- gut can potentiate disease (Table I). Until recently, IFN-I in tients in early or late stage and those with reduced survival (87). combination with antiviral drugs was standard treatment for Also, a gut virome analysis of patients displaying GVHD with chronic C virus infection and was associated with intestinal involvement revealed a marked increase in animal significant toxicity, including gastrointestinal illness. There is viruses with a DNA genome and bacteriophage richness (88). also evidence from case studies to suggest that IFN-I therapy In particular, the presence of a dsRNA Picobirnaviridae species may potentiate the development of celiac disease, an auto- is predictive of a severe enteric disease (88). The combined ap- that mainly occurs in individuals harboring proach of through deep sequencing and tar- HLA-DQ2 or DQ8 alleles in which inappropriate responses geted investigation of specific viral agents (like reovirus and to gluten leads to intestinal damage (73). This side effect of an- celiac disease) may be necessary to explore the contribution tiviral therapy is consistent with the observation that patients with of viruses to Crohn disease, GVHD, and other complex in- celiac disease display increased levels of IFN-I production by flammatory disorders that are likely influenced by multiple intestinal DCs that promote Th1 responses in the gut (74). It is infectious and genetic factors. therefore unsurprising that virus infections have long been sus- Downloaded from pected to be involved in the development of celiac disease (75). A Impact of intestinal viruses beyond the gastrointestinal tract compelling recent study demonstrated that celiac disease may be The impact of the intestinal virome may extend beyond caused by reoviruses, dsRNA viruses that commonly infect hu- the gastrointestinal tract to influence autoimmune diseases mansandaretypicallyassociatedwithmildorundetectable (Table I). One explanation for such extraintestinal effects of disease (76). In an animal model, reovirus infection blocked the viruses is the spread of infectious particles or viral RNA/DNA differentiation of peripheral regulatory T cells through IFN-I and from the intestine to other body sites. Indeed, the transit of http://www.jimmunol.org/ enhanced dietary Ag-specific Th1 responses through the tran- Ags between the gastrointestinal tract and pancreatic lymph scription factor IFN regulatory factor 1 (IRF1) (76). Patients nodes has been suggested as a mechanism for the effects of with celiac disease were also more likely to have higher anti- environmental agents on type 1 diabetes (T1D), an autoim- reovirus Ab titers, which was associated with higher expression mune disease where insulin-producing b cells are destroyed by of IRF1 in the small intestinal mucosa (76). Therefore, enteric pancreas-infiltrating autoreactive lymphocytes (89). Poly- viruses that are otherwise tolerated may induce serious intestinal morphisms in MDA5 (IFIH1) and an IFN-I gene expression disease in susceptible individuals. signature are associated with disease onset, supporting a role The paradigm of virus plus susceptibility gene interaction for viruses in disease progression (90, 91). Also, the appear- was initially demonstrated in experiments with MNV and re- ance of autoantibodies in patients correlates with infection by by guest on October 1, 2021 inforces the concept that viruses function as members of coxsackievirus B (CVB) 1, a positive-sense ssRNA virus that the gut microbiome. A common variant of ATG16L1,agene belongs to a diverse and prevalent group of that that mediates the cellular degradative pathway of autophagy, transmit fecal–orally (92). Infection with CVB3 and CVB6, is associated with increased susceptibility to a form of IBD which may provide cross-protection against CVB1, reduces known as Crohn disease. IBD is widely considered a disorder the risk of T1D development in prediabetic children (92). originating from a perturbed microbiome (77). Atg16L1 mu- Similar protection against virus-induced T1D is induced by CVB tant mice and Crohn disease patients harboring the ATG16L1 vaccination of mice (93). Although direct causation has not been risk allele display morphological defects in Paneth cells (78), established, CVB is believed to induce T1D by chronically antimicrobial epithelial cells in the small intestine that are es- infecting the pancreas and altering the local immune response sential for preventing inflammation (79). In the Atg16L1 (91). Rotavirus infection is also associated with progres- mutant mice, the Paneth cell defects and other inflammatory sion to T1D (94). In the NOD mouse model of T1D, oral pathologies were dependent on infection by MNV (78, 80). infection of adult mice with rotavirus leads to IFN-I–dependent In this model, loss of Atg16L1 in the intestinal epithelium bystander activation of lymphocytes in the pancreatic lymph sensitizes Paneth cells to necroptosis mediated by TNF-a nodes and acceleration of T1D onset, likely because of the spread produced in response to viral infection (81). MNV also of infectious virus to the mesenteric and pancreatic lymph nodes accelerates the onset of intestinal inflammation in mice de- (95–98). In contrast, neonatal infection of NOD mice with ro- ficient in the toxin transporter MDR1a that are colonized by tavirusorreovirusdelaystheonsetofdisease,suggestingthat Helicobacter bilis (82) and IL-10–deficient mice (83). Thus, timing of virus infections impacts the course of autoimmunity immune responses to an otherwise beneficial or innocuous (99, 100). virus can contribute to intestinal disease when combined A recent prospective study of infants at risk for T1D per- with genetic susceptibility. formed a longitudinal virome analysis and showed that increased Although host responses to MNV and Paneth cell properties bacteriophage diversity predicts a lack of progression to disease are likely conserved between mice and humans, further evi- (101). Increased bacteriophage diversity correlated with changes dence is required to support the role of IFN-I or the virome in in abundance of specific bacterial taxa, which may be related to Crohn disease. A number of other viruses, including entero- the extensive literature using NOD mice demonstrating that the virus, have been linked to Crohn disease (84, 85). In a virome composition of the bacterial microbiome is an important factor study, expansion of the Caudovirales bacteriophages in the gut in disease development (102). The same study also found was observed in Crohn disease patients (86). In this article, an enrichment of sequences belonging to in 1620 BRIEF REVIEWS: VIRAL COMPONENTS OF THE MICROBIOME the controls compared with individuals who develop T1D, mechanisms by which viruses at other sites of the body alter the raising the possibility that these group of poorly characterized immune system. Detailed immunological studies in mice have small ssDNA animal viruses are protective (101). Although supported a role for the IFN response but also highlight other these studies implicate multiple viruses in disease pathogen- pathways (Table II). Viruses that are traditionally considered esis, an exact mechanistic role for viruses in humans has yet to to display localized infection and disease can provoke systemic be established and requires additional research. responses, such as influenza A virus inducing hepatitis and Metagenomic studies of HIV-positive individuals have been intestinal damage without local infection (107, 108). Liver particularly informative in that they reveal the presence of a damage induced by influenza A virus is caused by the accumu- dynamic gut virome in a disease state. Low peripheral CD4 lation of pathogen-specific CD8+ T cells, and intestinal damage is cell counts lead to the development of AIDS, which is marked the result of an altered bacterial microbiome and increased IL-17a by increased susceptibility to secondary infection and other (107, 108). Therefore, an important possibility to examine is immunopathologies. The gut is a major site of HIV replication, whether enteric viruses select for T cells that exert pathological HIV-specific immune responses, and damage (103). Enteric outcomes once they migrate to other sites. adenoviruses and anelloviruses are increased in HIV-positive Latent viral infections may be a particularly potent mod- + patients with low peripheral CD4 T cell counts (104). Similar ulator of host responses. Gammaherpesvirus 68 (gHV-68) or expansion of the virome is observed in primates infected with CMV infection in mice enhances macrophage and NK cell SIV, with intestinal adenovirus associated with increased en- activation and improves the outcome of secondary infection teritis and parvovirus associated with increased pro- with Listeria monocytogenes, Yersinia pestis, and influenza A Downloaded from gression to AIDS (105). It is possible that this increased (109–111). In an animal model of primary immune defi- presence of viruses contributes to AIDS in a manner similar ciency, latent gHV-68 infection rescues survival follow- to the proposed role of the bacterial microbiome, where de- ing L. monocytogenes infection by inducing an inflammatory pletion of T cells in the gut disrupt the barrier, leading to the reaction that compensates for inadequate cytokine levels, systemic dissemination of bacterial products that fuel chronic suggesting that deleterious mutations can be masked by an and pathological immune activation (106). Given that the individual’s virome (112). gHV-68 also protects against http://www.jimmunol.org/ majority of humans by the time they reach adulthood become allergic asthma by altering the composition of macrophage transiently or chronically infected by the animal viruses subsets in the lung (113). In this case, the effect of viral discussed in this section (, ,and infection was not dependent on latent infection and oc- Picornaviridae), careful analysis of the gut virome in other curred during a developmental window. These findings in immune-related disorders is warranted. animal models are supported by elegant human cohort studies taking advantage of monozygotic twins with discrepancies in Lessons from extraintestinal virus infection their history of exposure to infectious agents. CMV infection When considering how the enteric virome might influence was identified as a particularly significant environmental interindividual variation, it is worth examining the known variable that influences a broad range of immune parameters by guest on October 1, 2021

Table II. Mechanisms by which extraintestinal viruses contribute to protection against or potentiation of diseases

Route of Virus Infection Model Outcome Mechanism Reference CMV i.p. Wild type mice Resistant to infection Latent infection, IFN-g (109) with the bacterial expression, and activation pathogens L. monocytogenes of systemic macrophages and Y. pestis Intestinal proliferation IFN-I–mediated Apol9a/b (72) expression Resistance to influenza Mediated by IFN-g expression (110) A infection 2 2 gHV-68 Intranasal HOIL-1 / mice Rescues lethality to Mediated by increased (112) L. monocytogenes proinflammatory cytokines i.p. Wild type mice Resistant to infection Latent infection, IFN-g (109) with the bacterial pathogens expression, and activation L. monocytogenes and Y. pestis of systemic macrophages Intranasal Wild type mice Protection from allergic Alteration of alveolar (113) asthma macrophage subsets Influenza A virus Respiratory Wild type mice Collateral liver damage Accumulation of virus-specific (107) CD8+ T cells in the liver Intestinal damage -dependent (108) expression of IL-17a in the intestine C Respiratory Humans Exacerbated asthma Use of a specific receptor, (123) CDHR3 (124) Respiratory Humans Cystic fibrosis Unknown (119) Blood Humans HIV disease protection Unknown (117) Examples discussed in this article by which extraintestinal viruses have unexpected immunomodulatory effects on the host are listed. As with intestinal viruses, these viruses can protect against infectious and noninfectious challenges while simultaneously increasing susceptibility to autoimmune or inflammatory diseases. These examples highlight the ability of viruses to affect tissue outside their replicative niche, sometimes long after the initial infection, and suggest that enteric viral infections may have similar consequences for the host. CDHR3, cadherin-related family member 3. The Journal of Immunology 1621

(114). Further, young adults previously exposed to CMV we can no longer ignore the possibility that they function as show a superior Ab and CD8+ T cell response to influenza components of the microbiome. Like bacteria, the effects that A vaccination (110). Thus, exposure to viruses can explain viruses have are critically dependent on their tissue location, interindividual heterogeneity when other factors fail to microenvironment, and host. These factors will directly in- provide an adequate explanation. fluence whether the virus acts beneficially, acts detrimentally, The blood virome of healthy individuals include or remains neutral for the host. With recent advances in meta- herpesviruses, anelloviruses, papillomaviruses, polyomaviruses, genomics coupled with techniques that enrich in sensitivity (1, 2, adenoviruses, parvoviruses, and pegivirus (115, 116). Al- 128), we can now perform large human studies with the aim of though it is unclear whether the presence of these viruses in linking changes in specific viral populations with disease patho- the blood is consequential, the inverse relationship between genesis. These studies can then support the development of more pegivirus and HIV disease progression suggests that deeper defined animal and cell culture studies that address the mecha- investigation of the blood virome will be fruitful (117). In nisms that individual viruses use to contribute to these pheno- contrast, there are a wealth of examples demonstrating that types. This research will certainly lead to the discovery of novel respiratory viruses cause or exacerbate chronic lung diseases. ways in which viruses interact with the host that we can poten- In cystic fibrosis patients who display altered mucus pro- tially harness for disease prevention and therapies. It may even be duction because of mutations in a chloride channel, disease is possible to engineer enteric viruses with desirable traits, much like associated with the presence of a core group of bacterio- current attempts at administering oncolytic viruses as adjuvants phages that infect bacterial species persistent in lungs (118). for cancer therapy (129–131). Cystic fibrosis patients also show increased susceptibility to Downloaded from infection with , whichislinkedtopoorrecovery Disclosures of lung function following flares (119–121). Respiratory The authors have no financial conflicts of interest. viruses are also linked to asthma (122). Patients have im- paired IFN-I responses following rhinovirus infection, and References rhinovirus C in particular is detectable in a significant pro- 1. Krishnamurthy, S. R., and D. Wang. 2017. Origins and challenges of viral dark portion of children with moderate to severe asthma (122, matter. 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