Norovirus Regulation by Host and Microbe
2016; Elsevier BV; Volume: 22; Issue: 12 Linguagem: Inglês
10.1016/j.molmed.2016.10.003
ISSN1471-499X
AutoresMegan T. Baldridge, Holly Turula, Christiane E. Wobus,
Tópico(s)Clostridium difficile and Clostridium perfringens research
ResumoMurine norovirus provides a practical model to study norovirus infections and pathogenesis. Murine and human noroviruses share a tropism for immune cells and intestinal epithelial cells. Norovirus infection is regulated by multiple host genes, including viral entry factors, innate immune mediators, and components of the adaptive immune system. The commensal bacteria of the gastrointestinal microbiome can modulate norovirus infection. Recent findings indicate that norovirus and commensal bacteria stimulate overlapping host immune pathways, and furthermore, that certain bacteria are required to mediate some of the pathologic effects of norovirus infection. Host and microbial effects on norovirus may function in complex combinations to regulate viral infection and pathogenesis. Norovirus (NoV) infection is the leading cause of epidemic gastroenteritis globally, and can lead to detrimental chronic infection in immunocompromised hosts. Despite its prevalence as a cause of diarrheal illness, the study of human NoVs (HNoVs) has historically been limited by a paucity of models. The use of murine NoV (MNoV) to interrogate mechanisms of host control of viral infection has facilitated the exploration of different genetic mouse models, revealing roles for both innate and adaptive immunity in viral regulation. MNoV studies have also recently identified important interactions between the commensal microbiota and NoV with clear extensions to HNoVs. In this review, we discuss the most current understanding of how the host, the microbiome, and their interactions regulate NoV infections. Norovirus (NoV) infection is the leading cause of epidemic gastroenteritis globally, and can lead to detrimental chronic infection in immunocompromised hosts. Despite its prevalence as a cause of diarrheal illness, the study of human NoVs (HNoVs) has historically been limited by a paucity of models. The use of murine NoV (MNoV) to interrogate mechanisms of host control of viral infection has facilitated the exploration of different genetic mouse models, revealing roles for both innate and adaptive immunity in viral regulation. MNoV studies have also recently identified important interactions between the commensal microbiota and NoV with clear extensions to HNoVs. In this review, we discuss the most current understanding of how the host, the microbiome, and their interactions regulate NoV infections. In the United States alone, human noroviruses (HNoVs) are responsible for approximately 20 million cases of acute gastroenteritis annually, leading to over 70 000 hospitalizations and nearly 800 deaths [1Hall A.J. et al.Norovirus disease in the United States.Emerg. Infect. Dis. 2013; 19: 1198-1205Crossref PubMed Scopus (425) Google Scholar]. HNoV infections are also a global problem, causing approximately US$60 billion in societal costs every year [2Bartsch S.M. et al.Global economic burden of norovirus gastroenteritis.PLoS ONE. 2016; 11: e0151219Crossref PubMed Scopus (305) Google Scholar]. HNoVs cause a species-specific infection, but recent developments are overcoming the historical lack of cell culture and small animal models [3Taube S. et al.A mouse model for human norovirus.mBio. 2013; 4: e00450-e513Crossref PubMed Scopus (140) Google Scholar, 4Jones M.K. et al.Enteric bacteria promote human and mouse norovirus infection of B cells.Science. 2014; 346: 755-759Crossref PubMed Scopus (580) Google Scholar, 5Ettayebi K. et al.Replication of human noroviruses in stem cell-derived human enteroids.Science. 2016; 353: 1387-1393Crossref PubMed Scopus (850) Google Scholar]. Nevertheless, the direct study of factors regulating HNoV pathogenesis in the natural host will always be limited. To counter this limitation, HNoV infections are studied in non-human hosts or related NoVs are investigated in their natural hosts as detailed in a recent review [6Wobus C.E. et al.Animal models of norovirus infection.in: Svensson L. Viral Gastroenteritis: Molecular Epidemiology and Pathogenesis. 1st. Academic Press, 2016: 397-422Crossref Scopus (10) Google Scholar]. Among the available models, murine NoV (MNoV), first described in 2003, provides the most widely used, readily tractable model system to explore viral and host factors regulating NoV infection [7Wobus C.E. et al.Murine norovirus: a model system to study norovirus biology and pathogenesis.J. Virol. 2006; 80: 5104-5112Crossref PubMed Scopus (459) Google Scholar]. MNoV infection is studied in vitro in macrophages, dendritic cells (DCs), and B cells [4Jones M.K. et al.Enteric bacteria promote human and mouse norovirus infection of B cells.Science. 2014; 346: 755-759Crossref PubMed Scopus (580) Google Scholar, 8Wobus C.E. et al.Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages.PLoS Biol. 2004; 2: e432Crossref PubMed Scopus (675) Google Scholar], as well as in vivo in mice [9Karst S.M. et al.STAT1-dependent innate immunity to a Norwalk-like virus.Science. 2003; 299: 1575-1578Crossref PubMed Scopus (649) Google Scholar]. Together, these studies have revealed novel host pathways critical to the regulation of NoV infection, and facilitated the exploration of NoV interactions with the commensal microbiome, a critically important player in mucosal infection. In this review, first, we briefly summarize parameters of NoV infections including transmission, symptoms, and viral tropism. Second, we explore the known mechanisms of host regulation of NoVs, with a focus on innate and adaptive immune regulators. Lastly, we detail recent work exploring the interactions of NoVs with the microbiota, describing the coordinate effects of host and microbial control of NoVs, and providing a comprehensive examination of the complex interactions between NoV, host, and bacteria. Future studies of the multifaceted regulation of NoV infection using existing and newly developed models will undoubtedly yield new scientific insights that may ultimately reduce the global burden of disease. NoV is a genus in the Caliciviridae (see Glossary) family. These non-enveloped icosahedral viruses have a single-stranded, positive-sense RNA genome, and are classified into at least six genogroups on the basis of their nucleotide sequence [10Green K.Y. Caliciviridae: the noroviruses.in: Knipe D.M. Fields Virology. 6th. Lippincott Williams & Wilkins, 2013: 582-608Google Scholar]. Genogroup I (GI), GII, and GIV viruses infect humans, with GII being the most prevalent, while GV viruses infect rodents (Table 1) [11Vinje J. Advances in laboratory methods for detection and typing of norovirus.J. Clin. Microbiol. 2015; 53: 373-381Crossref PubMed Scopus (591) Google Scholar]. The NoV genome contains three to four open reading frames (ORFs). ORF1 encodes nonstructural proteins including viral protein, genome-linked (VPg) and the RNA-dependent RNA polymerase (RdRp). ORF2 and ORF3 encode structural capsid proteins VP1 and VP2, respectively [10Green K.Y. Caliciviridae: the noroviruses.in: Knipe D.M. Fields Virology. 6th. Lippincott Williams & Wilkins, 2013: 582-608Google Scholar]. ORF4 is only found in MNoVs and encodes virulence factor VF1 [12McFadden N. et al.Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.PLoS Pathog. 2011; 7: e1002413Crossref PubMed Scopus (165) Google Scholar].Table 1Major Mechanisms of Infection in HNoV and MNoV. Human and murine norovirus (HNoV and MNoV) infections exhibit distinct characteristics, such as symptomatology and known attachment factors/receptors, but share overlap in the carbohydrate nature of their attachment factors, in cellular tropism, as well as in harboring a potential for persistent viral sheddingHuman norovirusMurine norovirusSymptomsAbdominal pain, nausea, vomiting, and diarrhea 17Newman K.L. et al.Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding.Clin. Exp. Immunol. 2016; 184: 347-357Crossref PubMed Scopus (38) Google Scholar, 20Kaufman S.S. et al.Treatment of norovirus infections: moving antivirals from the bench to the bedside.Antiviral Res. 2014; 105: 80-91Crossref PubMed Scopus (59) Google Scholar, 21Lee R.M. et al.Incubation periods of viral gastroenteritis: a systematic review.BMC Infect. Dis. 2013; 13: 446Crossref PubMed Scopus (113) Google ScholarAsymptomatic in wild-type mice; potential for lethality in immunocompromised mice (Table 2)Duration of infectionAcute symptomatic phase (1–4 days), which may be followed by viral shedding for weeks to months 22Teunis P.F. et al.Shedding of norovirus in symptomatic and asymptomatic infections.Epidemiol. Infect. 2015; 143: 1710-1717Crossref PubMed Scopus (156) Google Scholar, 23Echenique I.A. et al.Prolonged norovirus infection after pancreas transplantation: a case report and review of chronic norovirus.Transpl. Infect. Dis. 2016; 18: 98-104Crossref PubMed Scopus (23) Google Scholar, 24Karst S.M. et al.The molecular pathology of noroviruses.J. Pathol. 2015; 235: 206-216Crossref PubMed Scopus (56) Google ScholarAcute strains cleared in 7–10 days; persistent strains are shed for many months/lifetime of animal 24Karst S.M. et al.The molecular pathology of noroviruses.J. Pathol. 2015; 235: 206-216Crossref PubMed Scopus (56) Google Scholar, 30Karst S.M. et al.Advances in norovirus biology.Cell Host Microbe. 2014; 15: 668-680Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarIn vitro tropismB cells and enterocytes 4Jones M.K. et al.Enteric bacteria promote human and mouse norovirus infection of B cells.Science. 2014; 346: 755-759Crossref PubMed Scopus (580) Google Scholar, 5Ettayebi K. et al.Replication of human noroviruses in stem cell-derived human enteroids.Science. 2016; 353: 1387-1393Crossref PubMed Scopus (850) Google ScholarMacrophages, dendritic cells, microglial cells, and B cells 4Jones M.K. et al.Enteric bacteria promote human and mouse norovirus infection of B cells.Science. 2014; 346: 755-759Crossref PubMed Scopus (580) Google Scholar, 8Wobus C.E. et al.Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages.PLoS Biol. 2004; 2: e432Crossref PubMed Scopus (675) Google Scholar, 44Orchard R.C. et al.Discovery of a proteinaceous cellular receptor for a norovirus.Science. 2016; 353: 933-936Crossref PubMed Scopus (178) Google ScholarIn vivo tropismIntestinal epithelial cells, myeloid cells, and lymphoid cells in immunocompromised patients 40Karandikar U.C. et al.Detection of human norovirus in intestinal biopsies from immunocompromised transplant patients.J. Gen. Virol. 2016; 97: 2291-2300Crossref PubMed Scopus (65) Google ScholarIntestinal epithelial cells, macrophages, dendritic cells, B cells, and Kupffer cells (stellate macrophages in the liver) in immunocompromised mice 4Jones M.K. et al.Enteric bacteria promote human and mouse norovirus infection of B cells.Science. 2014; 346: 755-759Crossref PubMed Scopus (580) Google Scholar, 41Mumphrey S.M. et al.Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts, but clinical disease is prevented by STAT1-dependent interferon responses.J. Virol. 2007; 81: 3251-3263Crossref PubMed Scopus (178) Google Scholar, 42Ward J.M. et al.Pathology of immunodeficient mice with naturally occurring murine norovirus infection.Toxicol. Pathol. 2006; 34: 708-715Crossref PubMed Scopus (93) Google Scholar, 72Basic M. et al.Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice.Inflamm. Bowel Dis. 2014; 20: 431-443Crossref PubMed Scopus (101) Google ScholarKnown attachment factors and receptorsHisto-blood group antigens are attachment factors conferring susceptibility to most HNoV strains 51Tan M. Jiang X. Histo-blood group antigens: a common niche for norovirus and rotavirus.Expert Rev. Mol. Med. 2014; 16: e5Crossref PubMed Scopus (122) Google Scholar, 52Sestak K. Role of histo-blood group antigens in primate enteric calicivirus infections.World J. Virol. 2014; 3: 18-21Crossref PubMed Google Scholar. Some strains bind heparan sulfate, sialic acid, and β-galactosylceramide 81Bally M. et al.Norovirus GII.4 virus-like particles recognize galactosylceramides in domains of planar supported lipid bilayers.Angew. Chem. Int. Ed. Engl. 2012; 51: 12020-12024Crossref PubMed Scopus (30) Google Scholar, 82Rydell G.E. et al.Human noroviruses recognize sialyl Lewis × neoglycoprotein.Glycobiology. 2009; 19: 309-320Crossref PubMed Scopus (83) Google Scholar, 83Tamura M. et al.Genogroup II noroviruses efficiently bind to heparan sulfate proteoglycan associated with the cellular membrane.J. Virol. 2004; 78: 3817-3826Crossref PubMed Scopus (78) Google Scholar. No proteinaceous receptors are knownStrain-dependent attachment factors include terminal sialic acid residues on gangliosides and glycoproteins, and glycans on N-linked proteins 79Taube S. et al.Ganglioside-linked terminal sialic acid moieties on murine macrophages function as attachment receptors for murine noroviruses.J. Virol. 2009; 83: 4092-4101Crossref PubMed Scopus (156) Google Scholar, 80Taube S. et al.Murine noroviruses bind glycolipid and glycoprotein attachment receptors in a strain-dependent manner.J. Virol. 2012; 86: 5584-5593Crossref PubMed Scopus (63) Google Scholar; CD300LF and CD300LD are proteinaceous viral receptors 44Orchard R.C. et al.Discovery of a proteinaceous cellular receptor for a norovirus.Science. 2016; 353: 933-936Crossref PubMed Scopus (178) Google Scholar, 45Haga K. et al.Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: E6248-E6255Crossref PubMed Scopus (106) Google Scholar Open table in a new tab NoV transmission typically occurs by the fecal–oral route from contaminated surfaces, food or water, and by person-to-person spread [10Green K.Y. Caliciviridae: the noroviruses.in: Knipe D.M. Fields Virology. 6th. Lippincott Williams & Wilkins, 2013: 582-608Google Scholar] but transmission via droplets, through aerosolization of HNoV-containing vomitus, can also occur [13Kirby A.E. et al.Vomiting as a symptom and transmission risk in norovirus illness: evidence from human challenge studies.PLoS ONE. 2016; 11: e0143759Crossref PubMed Scopus (62) Google Scholar, 14Jones R.M. Brosseau L.M. Aerosol transmission of infectious disease.J. Occup. Environ. Med. 2015; 57: 501-508Crossref PubMed Scopus (222) Google Scholar]. Outbreaks occur in places where people gather (e.g., cruise ships, day-care centers, hospitals). They are facilitated by the low numbers of virions able to cause infections (i.e., low infectious dose) [15Teunis P.F. et al.Norwalk virus: how infectious is it?.J. Med. Virol. 2008; 80: 1468-1476Crossref PubMed Scopus (894) Google Scholar, 16Atmar R.L. et al.Determination of the 50% human infectious dose for Norwalk virus.J. Infect. 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After an average 1.2-day incubation period, HNoV infection induces symptoms including abdominal pain, nausea, vomiting, and diarrhea, which typically resolve within 1–4 days [17Newman K.L. et al.Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding.Clin. Exp. Immunol. 2016; 184: 347-357Crossref PubMed Scopus (38) Google Scholar, 20Kaufman S.S. et al.Treatment of norovirus infections: moving antivirals from the bench to the bedside.Antiviral Res. 2014; 105: 80-91Crossref PubMed Scopus (59) Google Scholar, 21Lee R.M. et al.Incubation periods of viral gastroenteritis: a systematic review.BMC Infect. Dis. 2013; 13: 446Crossref PubMed Scopus (113) Google Scholar]. However, viral shedding may occur for weeks to months in asymptomatic healthy hosts [22Teunis P.F. et al.Shedding of norovirus in symptomatic and asymptomatic infections.Epidemiol. Infect. 2015; 143: 1710-1717Crossref PubMed Scopus (156) Google Scholar], and years in immunocompromised patients [23Echenique I.A. et al.Prolonged norovirus infection after pancreas transplantation: a case report and review of chronic norovirus.Transpl. Infect. Dis. 2016; 18: 98-104Crossref PubMed Scopus (23) Google Scholar]. The latter have been postulated to serve as a reservoir for future outbreaks [24Karst S.M. et al.The molecular pathology of noroviruses.J. Pathol. 2015; 235: 206-216Crossref PubMed Scopus (56) Google Scholar]. There is no significant correlation between presentation of symptoms and viral burden, duration, or magnitude of NoV shedding, but enhanced cytokine responses correlate with HNoV symptoms and suggest immune mediation [17Newman K.L. et al.Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding.Clin. Exp. Immunol. 2016; 184: 347-357Crossref PubMed Scopus (38) Google Scholar]. Complications can occur following acute infection and include postinfectious irritable bowel syndrome [25Bonani M. et al.Chronic norovirus infection as a risk factor for secondary lactose maldigestion in renal transplant recipients: a prospective parallel cohort pilot study.Transplantation. 2016; (Published online August 1, 2016)https://doi.org/10.1097/TP.0000000000001376Crossref Scopus (11) Google Scholar, 26Futagami S. et al.Systematic review with meta-analysis: post-infectious functional dyspepsia.Aliment. Pharmacol. Ther. 2015; 41: 177-188Crossref PubMed Scopus (108) Google Scholar], life-threatening dehydration [27Glass R.I. et al.Norovirus gastroenteritis.N. Engl. J. Med. 2009; 361: 1776-1785Crossref PubMed Scopus (854) Google Scholar], necrotizing enterocolitis [28Pelizzo G. et al.Isolated colon ischemia with norovirus infection in preterm babies: a case series.J. Med. 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MNoV, a natural mouse pathogen endemic to animal facilities throughout the world [31Hsu C.C. et al.Development of a microsphere-based serologic multiplexed fluorescent immunoassay and a reverse transcriptase PCR assay to detect murine norovirus 1 infection in mice.Clin. Diagn. Lab. Immunol. 2005; 12: 1145-1151PubMed Google Scholar, 32Kim J.R. et al.Prevalence of murine norovirus infection in Korean laboratory animal facilities.J. Vet. Med. Sci. 2011; 73: 687-691Crossref PubMed Scopus (13) Google Scholar, 33McInnes E.F. et al.Prevalence of viral, bacterial and parasitological diseases in rats and mice used in research environments in Australasia over a 5-y period.Lab Anim. (NY). 2011; 40: 341-350Crossref PubMed Scopus (22) Google Scholar], has been the most widely used surrogate model. MNoV cultivation in multiple cell types in vitro, the ability to genetically manipulate both virus and host, and the use of acute [murine norovirus 1 (MNV-1)] and chronic (e.g., MNV.CR6, MNV-3) MNoV strains add to the strengths of this model system [24Karst S.M. et al.The molecular pathology of noroviruses.J. Pathol. 2015; 235: 206-216Crossref PubMed Scopus (56) Google Scholar, 30Karst S.M. et al.Advances in norovirus biology.Cell Host Microbe. 2014; 15: 668-680Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar]. The cellular and tissue tropism is a critical determinant of pathogenesis and an active area of investigation in the NoV field (Table 1) [34Karst S.M. Tibbetts S.A. Recent advances in understanding norovirus pathogenesis.J. Med. Virol. 2016; 88: 1837-1843Crossref PubMed Scopus (22) Google Scholar]. Recently, a model was proposed based on experimental evidence, whereby MNoVs use microfold (M) cells to overcome the epithelial barrier in order to infect B cells, macrophages, and DCs in the intestine, before being trafficked to local lymph nodes and distal sites by DCs [35Elftman M.D. et al.Multiple effects of dendritic cell depletion on murine norovirus infection.J. Gen. Virol. 2013; 94: 1761-1768Crossref PubMed Scopus (19) Google Scholar, 36Karst S.M. Wobus C.E. A working model of how noroviruses infect the intestine.PLoS Pathog. 2015; 11: e1004626Crossref PubMed Scopus (63) Google Scholar, 37Gonzalez-Hernandez M.B. et al.Efficient norovirus and reovirus replication in the mouse intestine requires microfold (M) cells.J. Virol. 2014; 88: 6934-6943Crossref PubMed Scopus (77) Google Scholar, 38Gonzalez-Hernandez M.B. et al.Murine norovirus transcytosis across an in vitro polarized murine intestinal epithelial monolayer is mediated by M-like cells.J. Virol. 2013; 87: 12685-12693Crossref PubMed Scopus (38) Google Scholar]. B cells are also targets for HNoVs [4Jones M.K. et al.Enteric bacteria promote human and mouse norovirus infection of B cells.Science. 2014; 346: 755-759Crossref PubMed Scopus (580) Google Scholar], but other targets exist, since humans deficient in B cells are still susceptible to HNoV infection [39Brown J.R. et al.Norovirus infections occur in B-cell-deficient patients.Clin. Infect. Dis. 2016; 62: 1136-1138Crossref PubMed Scopus (28) Google Scholar]. Recent immunofluorescence analysis of small intestinal biopsy samples from HNoV-infected immunocompromised patients revealed the presence of HNoV infection in intestinal epithelial cells, CD68+ or DC-SIGN+ phagocytes (e.g., macrophages, DCs), and CD3+ cells (T cells or intraepithelial lymphocytes) [40Karandikar U.C. et al.Detection of human norovirus in intestinal biopsies from immunocompromised transplant patients.J. Gen. Virol. 2016; 97: 2291-2300Crossref PubMed Scopus (65) Google Scholar]. A tropism of HNoV for enterocytes was subsequently confirmed by cultivating HNoV in human intestinal enteroid monolayer cultures [5Ettayebi K. et al.Replication of human noroviruses in stem cell-derived human enteroids.Science. 2016; 353: 1387-1393Crossref PubMed Scopus (850) Google Scholar]. MNoV antigen is also observed in small intestinal epithelial cells of immunodeficient signal transducer and activator of transcription 1 (Stat1)- and recombination activating gene (Rag1)/Stat1-deficient mice [41Mumphrey S.M. et al.Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts, but clinical disease is prevented by STAT1-dependent interferon responses.J. Virol. 2007; 81: 3251-3263Crossref PubMed Scopus (178) Google Scholar, 42Ward J.M. et al.Pathology of immunodeficient mice with naturally occurring murine norovirus infection.Toxicol. Pathol. 2006; 34: 708-715Crossref PubMed Scopus (93) Google Scholar]. Taken together, the data indicate that both MNoV and HNoVs share a tropism for intestinal immune and epithelial cells. However, whether all the same cell types are infected in immunocompetent hosts remains to be confirmed. Cellular tropism of NoVs is determined at the level of virus entry [43Guix S. et al.Norwalk virus RNA is infectious in mammalian cells.J. Virol. 2007; 81: 12238-12248Crossref PubMed Scopus (122) Google Scholar]. This was confirmed recently following the identification of CD300LF and CD300LD as functional receptors for MNoV [44Orchard R.C. et al.Discovery of a proteinaceous cellular receptor for a norovirus.Science. 2016; 353: 933-936Crossref PubMed Scopus (178) Google Scholar, 45Haga K. et al.Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: E6248-E6255Crossref PubMed Scopus (106) Google Scholar]. Expression of murine CD300LF and CD300LD in multiple nonsusceptible cells, including HeLa or HEK293T cells from nonmurine hosts, supported MNoV infection, while infection could be reduced by competition with soluble protein or antibody [44Orchard R.C. et al.Discovery of a proteinaceous cellular receptor for a norovirus.Science. 2016; 353: 933-936Crossref PubMed Scopus (178) Google Scholar, 45Haga K. et al.Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: E6248-E6255Crossref PubMed Scopus (106) Google Scholar]. Expression of human CD300F was unable to substitute for murine CD300LF, nor was antihuman CD300F able to block infection, indicating that restriction of NoVs may be due to species-specific variation in these molecules, rendering them determinants of species specificity. CD300LF and CD300LD belong to a family of type I transmembrane proteins with an immunoglobulin-like extracellular domain that can bind lipids in the plasma membrane [46Borrego F. The CD300 molecules: an emerging family of regulators of the immune system.Blood. 2013; 121: 1951-1960Crossref PubMed Scopus (147) Google Scholar]. Both proteins are expressed in myeloid cells, which are known MNoV target cells [47Tian L. et al.Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice.Cell Death Differ. 2016; 23: 1086-1096Crossref PubMed Scopus (24) Google Scholar, 48Albino D. et al.ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features.Cancer Res. 2012; 72: 2889-2900Crossref PubMed Scopus (96) Google Scholar]. These findings raise questions regarding their physiological role during MNoV infection in vivo. Preincubation of MNV-1 with soluble CD300LF prevents mortality of Stat1-deficient mice, and Cd300lf–/– mice are resistant to viral shedding following oral infection with MNV.CR6 [44Orchard R.C. et al.Discovery of a proteinaceous cellular receptor for a norovirus.Science. 2016; 353: 933-936Crossref PubMed Scopus (178) Google Scholar]. Whether MNoV establishes tissue infection in Cd300lf–/– or CD300ld–/– mice, however, has not been reported. These data pave the way for future investigations into the molecular details governing NoV entry. Another key player during NoV infection is fucosyltransferase 2, or FUT2, whose protein expression is critical for susceptibility to most (but not all) HNoV strains [49Currier R.L. et al.Innate susceptibility to norovirus infections influenced by FUT2 genotype in a United States pediatric population.Clin. Infect. Dis. 2015; 60: 1631-1638Crossref PubMed Scopus (82) Google Scholar, 50Lindesmith L. et al.Human susceptibility and resistance to Norwalk virus infection.Nat. Med. 2003; 9: 548-553Crossref PubMed Scopus (831) Google Scholar]. FUT2 activity is required during the synthesis of ABO histo-blood group antigens (HBGAs), which are attachment factors or receptors that facilitate binding of some caliciviruses to cells [51Tan M. Jiang X. Histo-blood group antigens: a common niche for norovirus and rotavirus.Expert Rev. Mol. Med. 2014; 16: e5Crossref PubMed Scopus (122) Google Scholar, 52Sestak K. Role of histo-blood group antigens in primate enteric calicivirus infections.World J. Virol. 2014; 3: 18-21Crossref PubMed Google Scholar]. Some individuals harbor an inactivating mutation in FUT2, which leads to the absence of ABO antigens, and these individuals (nonsecretors) have lower susceptibility to symptomatic infection [53Kambhampati A. et al.Host genetic susceptibility to enteric viruses: a systematic review and metaanalysis.Clin. Infect. Dis. 2016; 62: 11-18Crossref PubMed Scopus (80) Google Scholar]. This is likely due to the inability of certain HNoV strains to infect enterocytes, since intestinal organoids from nonsecretors are resistant to infection by some HNoVs [5Ettayebi K. et al.Replication of human noroviruses in stem cell-derived human enteroids.Science. 2016; 353: 1387-1393Crossref PubMed Scopus (850) Google Scholar]. Antibodies that prevent the interaction between the virus and HBGAs correlate with development of protective immune responses to HNoV infection [54Atmar R.L. et al.Norovirus vaccine against experimental human Norwalk virus illness.N. Engl. J. 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