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Virus interactions with mucosal surfaces: alternative receptors, alternative pathways
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Virus interactions with mucosal surfaces: alternative receptors, alternative pathways Jeffrey M Bergelson Viruses attach to specific receptors, but identified receptors are often absent from the epithelial surfaces where infections begin. Viruses can bind to alternative receptor molecules present on epithelial surfaces and they can enter hosts in ways that bypass mucosal barriers to infection. To understand how viruses cross the mucosa to initiate infection we need new information about the mechanisms of attachment and entry into cells, but we also need in vivo studies to define precisely where infection occurs. Addresses Division of Infectious Diseases, Children’s Hospital of Philadelphia, 1202 Abramson, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA e-mail: [email protected]
Current Opinion in Microbiology 2003, 6:386–391 This review comes from a themed issue on Host–microbe interactions: viruses Edited by Esteban Domingo 1369-5274/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/S1369-5274(03)00097-3
Abbreviations CAR coxsackievirus and adenovirus receptor CBV coxsackie B virus DAF decay-accelerating factor DC dendritic cell gal-cer galactosyl ceramide JAM junction adhesion molecule
Introduction Most virus infections begin when viruses interact with mucosal surfaces of the respiratory, genital, or gastrointestinal tracts. Some viral infections (for example rotavirus or influenza) are limited to the mucosa; in many others (such as measles, polio or HIV) virus crosses the mucosal surface and spreads to other organs. All mucosal surfaces present significant barriers to infection. Viscous fluids limit virus access to the cell surface, and a thick membrane-bound glycocalyx may serve a similar barrier function. Intercellular tight junctions inhibit virus access to subepithelial structures and to the basolateral surfaces of epithelial cells. Mucosal immunoglobulin [1,2] and antimicrobial peptides [3] inhibit virus growth. Nonetheless, viruses cross mucosal surfaces and invade. Expression of surface receptors that mediate viral attachment and entry into cells has for many years been Current Opinion in Microbiology 2003, 6:386–391
postulated to be essential for establishment of infection. Within the past decade, receptors have been identified for a variety of viruses [4]. However, in many cases the available information about receptors is insufficient to explain virus interaction with polarized epithelium. It has become evident that multiple receptors might be important for entry of a single virus, that receptor localization to specific membrane domains might be essential for function, and that virus access to receptors might be limited in particular tissues. Our ability to assess the importance of receptors for virus tropism depends on our knowledge of available receptors and their expression patterns, but also on a detailed description of virus infection and its spread in vivo. This information is not always easy to obtain. Until the HIV epidemic, the viral infection that received the most intense scrutiny was polio. In 1955, a series of experiments with chimpanzees led Bodian to conclude that the primary sites of poliovirus replication were the lymphoid tissues of the tonsils and intestinal tract [5] and that epithelial cell infection did not occur. The following year, Sabin concluded from experiments in animals and in human volunteers that poliovirus first infected the epithelium of the oropharynx and intestine [6]. Nearly fifty years later — although Bodian’s arguments seem to me more convincing, and although a variety of systems are available with which to study entry [7,8] — it is still not certain whether poliovirus infection in humans begins in the epithelium or in the mucosal lymphoid tissue. Studying the early events of infection in humans presents obvious difficulties and most of our available knowledge comes from model systems, which include in vitro cultures of epithelial cell lines, primary cultures, explanted tissues, transgenic animals and nonhuman primates. The architecture of different mucosal surfaces may differ widely, and results obtained with a particular model may or may not reflect the in vivo situation. In this review, I will attempt to summarize what we know about virus interactions with muscosal surfaces, with a particular focus on the receptor molecules involved; I will also point out areas where important information is lacking.
Features of mucosal surfaces The upper respiratory tract is lined by columnar epithelium (Figure 1a), with mature ciliated epithelial cells and immature basal cells in contact with a basement www.current-opinion.com
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Figure 1
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Organization of mucosal epithelium. (a) Ciliated columnar respiratory epithelium. (b) M cell overlying mucosal lymphoid tissue. (c) Stratified squamous epithelium of vagina. Dendritic cell process (red) reaches lumen.
membrane. The mature epithelial cells are highly polarized, so that the ciliated apical surface (exposed to the airway lumen) differs in structure and biochemical properties from the basolateral cell surfaces. Tight junctions between mature cells separate the apical and basolateral membranes and serve as a barrier to the paracellular transit of ions and macromolecules. In the small intestine, the deeply folded mucosal surface is lined by columnar epithelium with a microvillous brush border. Again, tight junctions prevent flow from the lumen. Within the submucosal layer, lymphoid follicles are covered by follicular epithelium containing specialized M cells [9]; these mediate the transcytosis of molecules, particles, and some bacterial and viral pathogens from the lumen to the underlying lymphoid tissue (Figure 1b). Although lymphoid follicles are most prominent in the small intestine — especially in the ileum, where they are called Peyer’s patches — mucosa-associated lymphoid tissue is present in the upper respiratory tract, and less organized lymphoid tissue is also distributed throughout other mucosa. Unlike the airway and intestine, the vagina is lined by stratified squamous epithelium, overlying a highly vascular submucosal layer rich in lymphocytes, macrophages and monocytes (Figure 1c). Intercellular junctions might not be as occlusive as those in the airway, but a lipid-rich extracellular fluid provides a physical barrier to flow across the epithelium. M cells are not evident; however, Langerhans dendritic cells (DCs) extend their processes to sample the lumenal contents and provide a potential route of virus entry. DCs may also mediate entry of pathogens at other mucosal sites [10]. www.current-opinion.com
Receptors expressed (or hypothesized) on the lumenal surface One might expect common respiratory viruses to replicate in respiratory epithelium. Consistent with its respiratory tropism, influenza virus binds to sialic acid on the apical surface and destroys polarized airway cells in culture [11]. Respiratory syncytial virus (RSV) infects cultured airway epithelia via the apical surface; infection appears specific for ciliated cells and does not spread to basal cells [11]. Parainfluenza virus enters both the apical and basolateral surfaces of polarized A549 cells, which have characteristics of surfactant-secreting type II pneumocytes [12]. The specific receptors responsible for infection by RSV and parainfluenza have not been identified, but are likely to be present on the apical surface.
Receptor expression that does not explain epithelial tropism Measles is transmitted by the respiratory route. The measles virus has been reported to replicate in the epithelium of the respiratory tract, where it is then transmitted to lymphoid cells and spreads systemically [13]. Measles virus interacts with at least two receptors. Many primary isolates are restricted in their tropism and require interaction with CD150 [14], a molecule expressed on lymphoid and DCs but not on respiratory epithelium [13]. Isolates adapted to tissue culture cells can use CD46, a molecule expressed on virtually all nucleated human cells. Although CD46-adapted measles enters the apical surface of polarized intestinal and renal cell lines, it preferentially infects the basolateral surface of primary respiratory epithelial cells, despite the apical expression of CD46 [15]. Thus, the identified receptor for wild-type viruses is absent from the respiratory epithelium and the Current Opinion in Microbiology 2003, 6:386–391
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presence of a functional receptor does not explain the polarization of entry. Alternative receptors or alternative routes of entry might be important in vivo, and physical barriers — such as the glycocalyx — could prevent access to apical receptors.
Receptors sequestered in intercellular junctions The respiratory tropism of adenoviruses is also poorly understood. Although adenoviruses are respiratory pathogens, and were assumed to infect the airway epithelium, intensive efforts to use adenovirus vectors for gene delivery to the airway have not been successful. Adenoviruses infect a variety of epithelial cells in vitro, and human airway epithelial cells — when dispersed and sparsely plated — are susceptible to transduction by adenovirus gene delivery vectors. However, differentiated airway epithelium resists transduction by adenovirus vectors delivered to the apical surface [16]. Airway cells express the coxsackievirus and adenovirus receptor (CAR), but once a mature ciliated epithelium is formed, CAR molecules are excluded from the apical surface [17,18], and largely confined to intercellular tight junctions where they are inaccessible to the virus [19]. Disruption of tight junctions exposes CAR and restores susceptibility to infection. Similarly, expression of retargeted CAR on the apical surface renders airway epithelia susceptible to infection [20] (although access to apical receptors may still be inhibited by physical factors, such as the glycocalyx) [21]. Much of what we know has been derived from studies of gene delivery using non-replicating vectors. It is possible that with replicating virus, even a very inefficient entry pathway, or small breaks in the epithelial surface, might be sufficient to permit infection and spread. However, it is not certain that clinical adenovirus infections normally involve those regions of the airway targeted in the gene therapy experiments. Coxsackie B viruses also use CAR as a receptor, and CARdependent CBV infect polarized epithelial cells only when tight junctions are disrupted [19]. Reoviruses use another tight junction molecule, junction adhesion molecule (JAM), as a receptor [22]; it is not yet certain if JAM localization is an obstacle to infection in polarized cells. An adherens junction protein, nectin-1, mediates cell entry by herpes simplex virus, and nectin, like CAR, is inaccessible to the virus unless junctions are disrupted [23]. It thus appears that several viruses have evolved to use receptors that are sequestered in intracellular junctions.
Other virus–junction interactions Viruses have also evolved specific mechanisms to modulate junctions. Rotavirus disrupts tight junctions [24]; the increase in transepithelial permeability, a function of the viral toxin NSP4, might contribute to the pathogenesis of virus-induced diarrhea and transmission within the Current Opinion in Microbiology 2003, 6:386–391
community, although it is not evident that it results in increased cell-to-cell spread. Adenovirus fiber protein, which mediates virus attachment to CAR, disrupts tight junctions when it is applied to the basolateral surface of polarized respiratory epithelium [25] — most likely by interfering with CAR-mediated cell adhesion. The disruption of junctions could permit virus spread from the basal surface to the lumen, although it is not certain how the virus reaches the basal surface in vivo. Inflammatory cytokines modulate the structure and function of tight junctions [26], so virus infection might also disrupt junctions by indirect mechanisms. Interaction with junctional proteins may promote cell-tocell spread within an epithelium. Nascent herpes simplex and pseudorabies virus particles are sorted to lateral cell junctions, so that budding virus is well situated to interact with receptors on the lateral surface of neighboring cells [27]. Lateral sorting depends on the viral gE/gI glycoprotein complex, and gE mutants spread poorly in neurons and polarized epithelial cells. The homologous gE protein of varicella-zoster virus (VZV) associates with components of tight junctions and contributes to decreased epithelial permeability [28]; although its function has not been confirmed, it is reasonable to suspect that VZV gE might also facilitate virus spread.
Use of alternative receptors Coxsackieviruses, such as polioviruses and other enteroviruses, are thought to be transmitted across the gastrointestinal mucosa. Although all CBVs interact with CAR, a subset of CBV attach to an additional molecule, decayaccelerating factor (DAF); other enteroviruses appear to have independently evolved the capacity to bind to DAF [29]. Expression of human DAF mediates virus attachment to transfected rodent cells, but no infection is seen in the absence of CAR. It has therefore been somewhat difficult to understand the possible function of DAF interaction. DAF is highly expressed on the apical surface of polarized epithelium, and DAF-binding CBV can attach to and infect polarized cells despite the inaccessibility of CAR [30]. Growth on polarized epithelial cells selects for CAR-binding viral variants, suggesting that interaction with mucosal surfaces might be important in the widespread capacity of enteroviruses to bind DAF. It is possible that DAF-binding viruses directly infect intestinal epithelium, whereas other isolates infect by alternative routes, such as transcytosis across M cells [8]. Alternative receptors may be involved in entry by other viruses that interact with sequestered junctional molecules. Adenovirus interaction with integrins [31], with heparan sulfate proteoglycans [32], and with phospholipds [33] can permit virus entry in the absence of CAR. Some reoviruses bind to sialic acid as well as to JAM [34], www.current-opinion.com
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and it is conceivable that interaction with sialic acid, which is expressed primarily on the apical surface of polarized epithelium [35], permits the virus to infect despite the inaccessibility of the primary receptor. A variety of viruses are capable of binding to highly expressed glycoproteins and glycolipids, and this lectin-like activity may be important in determining tropism [4]. The murine model of reovirus infection may be particularly well suited to determining the in vivo functional roles of alternative receptors. Epstein Barr virus (EBV) primarily infects B lymphocytes, but EBV infection of epithelial cells of the oropharynx may be important in initial infection, transmission and the pathogenesis of nasopharyngeal carcinoma. The primary EBV receptor is a B cell molecule, CD21 [36], which is not expressed on oral epithelium. Virus spread from lymphocyte to the basal surface of polarized epithelium depends on interaction with cell-surface integrins (avb3/b5 and a5b1) rather than with
CD21 [37]. Virus emerging from epithelial cells appears to differ in surface composition from B-cell-derived virus; alterations in the complement of cell-surface glycoproteins may promote tropism for specific target cells [38].
HIV entry: alternative receptors, alternative pathways HIV is transmitted across mucosal epithelium lining the rectum, vagina, or upper respiratory tract; a variety of possible mechanisms have been proposed to explain how this occurs (Figure 2). For example, breaks within the epithelium might permit virus to interact directly with submucosal target cells, or virus-infected lymphocytes or macrophages within the lumen may migrate across the epithelium [39]. Although epithelial cells lack expression of the primary receptor, CD4, galactosyl ceramide (gal-cer) on these cells permits virus attachment [40], and expression of an appropriate coreceptor (CXCR4 or CCR5) permits
Figure 2
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Potential mechanisms by which HIV may cross mucosal epithelium. (a) Break in epithelium permits virus (green) to reach submucosal lymphocyte. (b) Direct infection of epithelium, with replication and spread. (c) Transcytosis across epithelium. (d) Transcytosis through M cells. (e) Virus transport on dendritic cell process (red). (f) Transepithelial migration of infected macrophage. www.current-opinion.com
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infection of polarized epithelial cell lines. However, it is not clear if epithelial infection is important in vivo. When simian immunodeficiency virus (SIV) is applied to the tonsillar surface of macaques, infectious virus appears rapidly within the T cells underlying tonsillar crypts, but no infection is seen in the epithelium itself [41]. In cultures of polarized epithelium, lymphocyte-associated (but not cell-free) virus is rapidly delivered to the basal surface by a process of transcytosis, suggesting a mechanism by which cell-associated virus could be presented to submucosal lymphocytes in the absence of epithelial infection [42]. M cell mediated transcytosis may occur. Co-cultivation of intestinal epithelial cells with lymphocytes in vitro leads to the generation of M-like cells capable of efficient transcytosis of particles and bacteria [43]. Such in vitro-derived M cells rapidly transport cell-free HIV from the apical to the lumenal surface of intestinal epithelial cells by a mechanism that requires virus interaction both with gal-cer and with chemokine receptors [44]. Primary intestinal epithelial cells express both gal-cer and CCR5, but unlike some cell lines, they do not express CXCR4; in consequence, they permit transcytosis only of HIV isolates capable of interaction with CCR5 [45]. Such R5 strains are those associated with early infection. CCR5-dependent transcytosis and presentation to subepithelial T cells could act as a filter, accounting for the limited transmission of CXCR4dependent isolates from chronically infected patients. Aside from their importance for HIV pathogenesis, these results suggest that M-cell interactions with other viruses may be highly specific; the receptor interactions necessary for uptake by M cells will be of obvious interest. Within the vagina, DCs may be susceptible to direct infection by lumenal virus. In one report, infection of CD4þ T-cells, but not of DCs, was observed three days after intravaginal delivery of SIV to macaques [46]; however, other investigators found that DCs became infected within hours of vaginal exposure, and then migrated rapidly to regional lymph nodes [47]. Intraepithelial Langerhans cells appeared to be infected first [47]; subepithelial DCs expressing the alternative receptor DCSIGN [48] are likely to be involved in the spread of infection to other lymphoid cells.
Conclusions As demonstrated by the HIV studies, viruses may cross mucosal barriers by a variety of mechanisms. Transmission of HIV in humans is likely to involve several of these, with some more important at particular anatomic sites; alternatively, some of the reported mechanisms may operate only in experimental systems. Understanding of how viruses actually infect will require new information about the molecular mechanisms of attachment and entry. Even more important will be detailed information about precisely what cell types and tissues are infected in vivo. Current Opinion in Microbiology 2003, 6:386–391
Acknowledgements My work on virus interactions with polarized epithelium has been supported by the NIH, the Cystic Fibrosis Foundation and the American Heart Association. I thank Susan Coffin for her comments. I apologize to any investigators whose work I have omitted or inadvertently misunderstood.
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34. Chappell JD, Duong JL, Wright BW, Dermody TS: Identification of carbohydrate-binding domains in the attachment proteins of type 1 and type 3 reoviruses. J Virol 2000, 74:8472-8479. 35. Ciarlet M, Crawford SE, Estes MK: Differential infection of polarized epithelial cell lines by sialic acid-dependent and sialic acid-independent rotavirus strains. J Virol 2001, 75:11834-11850. 36. Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT: Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor, CR2. Proc Natl Acad Sci USA 1984, 81:4510. 37. Tugizov SM, Berline JW, Palefsky JM: Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nat Med 2003, 9:307-314. Demonstrates CD21-independent pathways by which Epstein-Barr virus may infect epithelium. 38. Borza CM, Hutt-Fletcher LM: Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 2002, 8:594-599. 39. Carreno MP, Chamont N, Kazatchkine MD, Irinopoulou T, Krief C, Mohamed A-S, Andreoletti L, Matta M, Belec L: Binding of LFA-1 (CD11a) to intracellular adhesion molecule 3 (ICAM-3, CD50) and ICAM-2 (CD102) triggers transmigration of human immunodeficiency virus type type 1-infected monocytes through mucosal epithelial cells. J Virol 2002, 76:32-40. 40. Fantini J, Cook DG, Nathanson N, Spitalnik SL, GonzalezScarano F: Infection of colonic epithelial cell lines by type 1 human immunodeficiency virus is associated with cell surface expression of galactosylceramide, a potential alternative gp120 receptor. Proc Natl Acad Sci USA 1993, 90:2700-2704. 41. Stahl-Hennig C, Steinman RM, Tenner-Racz K, Pope M, Stolte N, Ma¨ tz-Rensing K, Grobschupff G, Raschdorff B, Hunsmann G, Racz P: Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus. Science 1999, 285:1261-1265. 42. Bomsel M: Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nat Med 1997, 3:42-47. 43. Kerne´ is S, Bogdanova A, Kraehenbuhl J-P, Pringault E: Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 1997, 277:949-952. 44. Fotopoulos G, Harari A, Michetti P, Trono D, Pantaleo G, Kraehenbuhl J-P: Transepithelial transport of HIV-1 by M cells is receptor-mediated. Proc Natl Acad Sci USA 2002, 99:9410-9414. See annotation to Meng et al. (2002) [45]. 45. Meng G, Wei X, Wu X, Sellers MT, Decker JM, Moldoveanu Z, Orenstein JM, Graham MF, Kappes JC, Mestecky J et al.: Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5R cells. Nat Med 2002, 8:150-156. This paper and the preceding paper use an in vitro model of M-cell development (described in reference 43) to demonstrate that transcytosis requires specific receptor interactions. The requirement for chemokine receptor expression on the target cell suggests the possibility that fusion of viral and cellular membranes may somehow be involved. The results also suggest a possible mechanism for the selective transmission of R5 viruses. 46. Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA, Reinhart TA, Rogan M, Cavert W, Miller CJ et al.: Sexual transmission and propagation of SIV and HIV in resting and activated CD4R T cells. Science 1999, 286:1353-1357. 47. Hu J, Gardner MB, Miller CJ: Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 2000, 74:6087-6095. 48. Geijtenbeek TBH, Kwon DS, Torensma R, van Vliet SJ, Cornelissen ILMHA, Nottet HSLM, Kewal Ramani VN, Littman DR, Figdor CG, van Kooyk Y: DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000, 100:587-597. Current Opinion in Microbiology 2003, 6:386–391
Virus interactions with mucosal surfaces: alternative receptors, alternative pathways Jeffrey M Bergelson Viruses attach to specific receptors, but identified receptors are often absent from the epithelial surfaces where infections begin. Viruses can bind to alternative receptor molecules present on epithelial surfaces and they can enter hosts in ways that bypass mucosal barriers to infection. To understand how viruses cross the mucosa to initiate infection we need new information about the mechanisms of attachment and entry into cells, but we also need in vivo studies to define precisely where infection occurs. Addresses Division of Infectious Diseases, Children’s Hospital of Philadelphia, 1202 Abramson, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA e-mail: [email protected]
Current Opinion in Microbiology 2003, 6:386–391 This review comes from a themed issue on Host–microbe interactions: viruses Edited by Esteban Domingo 1369-5274/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/S1369-5274(03)00097-3
Abbreviations CAR coxsackievirus and adenovirus receptor CBV coxsackie B virus DAF decay-accelerating factor DC dendritic cell gal-cer galactosyl ceramide JAM junction adhesion molecule
Introduction Most virus infections begin when viruses interact with mucosal surfaces of the respiratory, genital, or gastrointestinal tracts. Some viral infections (for example rotavirus or influenza) are limited to the mucosa; in many others (such as measles, polio or HIV) virus crosses the mucosal surface and spreads to other organs. All mucosal surfaces present significant barriers to infection. Viscous fluids limit virus access to the cell surface, and a thick membrane-bound glycocalyx may serve a similar barrier function. Intercellular tight junctions inhibit virus access to subepithelial structures and to the basolateral surfaces of epithelial cells. Mucosal immunoglobulin [1,2] and antimicrobial peptides [3] inhibit virus growth. Nonetheless, viruses cross mucosal surfaces and invade. Expression of surface receptors that mediate viral attachment and entry into cells has for many years been Current Opinion in Microbiology 2003, 6:386–391
postulated to be essential for establishment of infection. Within the past decade, receptors have been identified for a variety of viruses [4]. However, in many cases the available information about receptors is insufficient to explain virus interaction with polarized epithelium. It has become evident that multiple receptors might be important for entry of a single virus, that receptor localization to specific membrane domains might be essential for function, and that virus access to receptors might be limited in particular tissues. Our ability to assess the importance of receptors for virus tropism depends on our knowledge of available receptors and their expression patterns, but also on a detailed description of virus infection and its spread in vivo. This information is not always easy to obtain. Until the HIV epidemic, the viral infection that received the most intense scrutiny was polio. In 1955, a series of experiments with chimpanzees led Bodian to conclude that the primary sites of poliovirus replication were the lymphoid tissues of the tonsils and intestinal tract [5] and that epithelial cell infection did not occur. The following year, Sabin concluded from experiments in animals and in human volunteers that poliovirus first infected the epithelium of the oropharynx and intestine [6]. Nearly fifty years later — although Bodian’s arguments seem to me more convincing, and although a variety of systems are available with which to study entry [7,8] — it is still not certain whether poliovirus infection in humans begins in the epithelium or in the mucosal lymphoid tissue. Studying the early events of infection in humans presents obvious difficulties and most of our available knowledge comes from model systems, which include in vitro cultures of epithelial cell lines, primary cultures, explanted tissues, transgenic animals and nonhuman primates. The architecture of different mucosal surfaces may differ widely, and results obtained with a particular model may or may not reflect the in vivo situation. In this review, I will attempt to summarize what we know about virus interactions with muscosal surfaces, with a particular focus on the receptor molecules involved; I will also point out areas where important information is lacking.
Features of mucosal surfaces The upper respiratory tract is lined by columnar epithelium (Figure 1a), with mature ciliated epithelial cells and immature basal cells in contact with a basement www.current-opinion.com
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Figure 1
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Organization of mucosal epithelium. (a) Ciliated columnar respiratory epithelium. (b) M cell overlying mucosal lymphoid tissue. (c) Stratified squamous epithelium of vagina. Dendritic cell process (red) reaches lumen.
membrane. The mature epithelial cells are highly polarized, so that the ciliated apical surface (exposed to the airway lumen) differs in structure and biochemical properties from the basolateral cell surfaces. Tight junctions between mature cells separate the apical and basolateral membranes and serve as a barrier to the paracellular transit of ions and macromolecules. In the small intestine, the deeply folded mucosal surface is lined by columnar epithelium with a microvillous brush border. Again, tight junctions prevent flow from the lumen. Within the submucosal layer, lymphoid follicles are covered by follicular epithelium containing specialized M cells [9]; these mediate the transcytosis of molecules, particles, and some bacterial and viral pathogens from the lumen to the underlying lymphoid tissue (Figure 1b). Although lymphoid follicles are most prominent in the small intestine — especially in the ileum, where they are called Peyer’s patches — mucosa-associated lymphoid tissue is present in the upper respiratory tract, and less organized lymphoid tissue is also distributed throughout other mucosa. Unlike the airway and intestine, the vagina is lined by stratified squamous epithelium, overlying a highly vascular submucosal layer rich in lymphocytes, macrophages and monocytes (Figure 1c). Intercellular junctions might not be as occlusive as those in the airway, but a lipid-rich extracellular fluid provides a physical barrier to flow across the epithelium. M cells are not evident; however, Langerhans dendritic cells (DCs) extend their processes to sample the lumenal contents and provide a potential route of virus entry. DCs may also mediate entry of pathogens at other mucosal sites [10]. www.current-opinion.com
Receptors expressed (or hypothesized) on the lumenal surface One might expect common respiratory viruses to replicate in respiratory epithelium. Consistent with its respiratory tropism, influenza virus binds to sialic acid on the apical surface and destroys polarized airway cells in culture [11]. Respiratory syncytial virus (RSV) infects cultured airway epithelia via the apical surface; infection appears specific for ciliated cells and does not spread to basal cells [11]. Parainfluenza virus enters both the apical and basolateral surfaces of polarized A549 cells, which have characteristics of surfactant-secreting type II pneumocytes [12]. The specific receptors responsible for infection by RSV and parainfluenza have not been identified, but are likely to be present on the apical surface.
Receptor expression that does not explain epithelial tropism Measles is transmitted by the respiratory route. The measles virus has been reported to replicate in the epithelium of the respiratory tract, where it is then transmitted to lymphoid cells and spreads systemically [13]. Measles virus interacts with at least two receptors. Many primary isolates are restricted in their tropism and require interaction with CD150 [14], a molecule expressed on lymphoid and DCs but not on respiratory epithelium [13]. Isolates adapted to tissue culture cells can use CD46, a molecule expressed on virtually all nucleated human cells. Although CD46-adapted measles enters the apical surface of polarized intestinal and renal cell lines, it preferentially infects the basolateral surface of primary respiratory epithelial cells, despite the apical expression of CD46 [15]. Thus, the identified receptor for wild-type viruses is absent from the respiratory epithelium and the Current Opinion in Microbiology 2003, 6:386–391
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presence of a functional receptor does not explain the polarization of entry. Alternative receptors or alternative routes of entry might be important in vivo, and physical barriers — such as the glycocalyx — could prevent access to apical receptors.
Receptors sequestered in intercellular junctions The respiratory tropism of adenoviruses is also poorly understood. Although adenoviruses are respiratory pathogens, and were assumed to infect the airway epithelium, intensive efforts to use adenovirus vectors for gene delivery to the airway have not been successful. Adenoviruses infect a variety of epithelial cells in vitro, and human airway epithelial cells — when dispersed and sparsely plated — are susceptible to transduction by adenovirus gene delivery vectors. However, differentiated airway epithelium resists transduction by adenovirus vectors delivered to the apical surface [16]. Airway cells express the coxsackievirus and adenovirus receptor (CAR), but once a mature ciliated epithelium is formed, CAR molecules are excluded from the apical surface [17,18], and largely confined to intercellular tight junctions where they are inaccessible to the virus [19]. Disruption of tight junctions exposes CAR and restores susceptibility to infection. Similarly, expression of retargeted CAR on the apical surface renders airway epithelia susceptible to infection [20] (although access to apical receptors may still be inhibited by physical factors, such as the glycocalyx) [21]. Much of what we know has been derived from studies of gene delivery using non-replicating vectors. It is possible that with replicating virus, even a very inefficient entry pathway, or small breaks in the epithelial surface, might be sufficient to permit infection and spread. However, it is not certain that clinical adenovirus infections normally involve those regions of the airway targeted in the gene therapy experiments. Coxsackie B viruses also use CAR as a receptor, and CARdependent CBV infect polarized epithelial cells only when tight junctions are disrupted [19]. Reoviruses use another tight junction molecule, junction adhesion molecule (JAM), as a receptor [22]; it is not yet certain if JAM localization is an obstacle to infection in polarized cells. An adherens junction protein, nectin-1, mediates cell entry by herpes simplex virus, and nectin, like CAR, is inaccessible to the virus unless junctions are disrupted [23]. It thus appears that several viruses have evolved to use receptors that are sequestered in intracellular junctions.
Other virus–junction interactions Viruses have also evolved specific mechanisms to modulate junctions. Rotavirus disrupts tight junctions [24]; the increase in transepithelial permeability, a function of the viral toxin NSP4, might contribute to the pathogenesis of virus-induced diarrhea and transmission within the Current Opinion in Microbiology 2003, 6:386–391
community, although it is not evident that it results in increased cell-to-cell spread. Adenovirus fiber protein, which mediates virus attachment to CAR, disrupts tight junctions when it is applied to the basolateral surface of polarized respiratory epithelium [25] — most likely by interfering with CAR-mediated cell adhesion. The disruption of junctions could permit virus spread from the basal surface to the lumen, although it is not certain how the virus reaches the basal surface in vivo. Inflammatory cytokines modulate the structure and function of tight junctions [26], so virus infection might also disrupt junctions by indirect mechanisms. Interaction with junctional proteins may promote cell-tocell spread within an epithelium. Nascent herpes simplex and pseudorabies virus particles are sorted to lateral cell junctions, so that budding virus is well situated to interact with receptors on the lateral surface of neighboring cells [27]. Lateral sorting depends on the viral gE/gI glycoprotein complex, and gE mutants spread poorly in neurons and polarized epithelial cells. The homologous gE protein of varicella-zoster virus (VZV) associates with components of tight junctions and contributes to decreased epithelial permeability [28]; although its function has not been confirmed, it is reasonable to suspect that VZV gE might also facilitate virus spread.
Use of alternative receptors Coxsackieviruses, such as polioviruses and other enteroviruses, are thought to be transmitted across the gastrointestinal mucosa. Although all CBVs interact with CAR, a subset of CBV attach to an additional molecule, decayaccelerating factor (DAF); other enteroviruses appear to have independently evolved the capacity to bind to DAF [29]. Expression of human DAF mediates virus attachment to transfected rodent cells, but no infection is seen in the absence of CAR. It has therefore been somewhat difficult to understand the possible function of DAF interaction. DAF is highly expressed on the apical surface of polarized epithelium, and DAF-binding CBV can attach to and infect polarized cells despite the inaccessibility of CAR [30]. Growth on polarized epithelial cells selects for CAR-binding viral variants, suggesting that interaction with mucosal surfaces might be important in the widespread capacity of enteroviruses to bind DAF. It is possible that DAF-binding viruses directly infect intestinal epithelium, whereas other isolates infect by alternative routes, such as transcytosis across M cells [8]. Alternative receptors may be involved in entry by other viruses that interact with sequestered junctional molecules. Adenovirus interaction with integrins [31], with heparan sulfate proteoglycans [32], and with phospholipds [33] can permit virus entry in the absence of CAR. Some reoviruses bind to sialic acid as well as to JAM [34], www.current-opinion.com
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and it is conceivable that interaction with sialic acid, which is expressed primarily on the apical surface of polarized epithelium [35], permits the virus to infect despite the inaccessibility of the primary receptor. A variety of viruses are capable of binding to highly expressed glycoproteins and glycolipids, and this lectin-like activity may be important in determining tropism [4]. The murine model of reovirus infection may be particularly well suited to determining the in vivo functional roles of alternative receptors. Epstein Barr virus (EBV) primarily infects B lymphocytes, but EBV infection of epithelial cells of the oropharynx may be important in initial infection, transmission and the pathogenesis of nasopharyngeal carcinoma. The primary EBV receptor is a B cell molecule, CD21 [36], which is not expressed on oral epithelium. Virus spread from lymphocyte to the basal surface of polarized epithelium depends on interaction with cell-surface integrins (avb3/b5 and a5b1) rather than with
CD21 [37]. Virus emerging from epithelial cells appears to differ in surface composition from B-cell-derived virus; alterations in the complement of cell-surface glycoproteins may promote tropism for specific target cells [38].
HIV entry: alternative receptors, alternative pathways HIV is transmitted across mucosal epithelium lining the rectum, vagina, or upper respiratory tract; a variety of possible mechanisms have been proposed to explain how this occurs (Figure 2). For example, breaks within the epithelium might permit virus to interact directly with submucosal target cells, or virus-infected lymphocytes or macrophages within the lumen may migrate across the epithelium [39]. Although epithelial cells lack expression of the primary receptor, CD4, galactosyl ceramide (gal-cer) on these cells permits virus attachment [40], and expression of an appropriate coreceptor (CXCR4 or CCR5) permits
Figure 2
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Potential mechanisms by which HIV may cross mucosal epithelium. (a) Break in epithelium permits virus (green) to reach submucosal lymphocyte. (b) Direct infection of epithelium, with replication and spread. (c) Transcytosis across epithelium. (d) Transcytosis through M cells. (e) Virus transport on dendritic cell process (red). (f) Transepithelial migration of infected macrophage. www.current-opinion.com
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infection of polarized epithelial cell lines. However, it is not clear if epithelial infection is important in vivo. When simian immunodeficiency virus (SIV) is applied to the tonsillar surface of macaques, infectious virus appears rapidly within the T cells underlying tonsillar crypts, but no infection is seen in the epithelium itself [41]. In cultures of polarized epithelium, lymphocyte-associated (but not cell-free) virus is rapidly delivered to the basal surface by a process of transcytosis, suggesting a mechanism by which cell-associated virus could be presented to submucosal lymphocytes in the absence of epithelial infection [42]. M cell mediated transcytosis may occur. Co-cultivation of intestinal epithelial cells with lymphocytes in vitro leads to the generation of M-like cells capable of efficient transcytosis of particles and bacteria [43]. Such in vitro-derived M cells rapidly transport cell-free HIV from the apical to the lumenal surface of intestinal epithelial cells by a mechanism that requires virus interaction both with gal-cer and with chemokine receptors [44]. Primary intestinal epithelial cells express both gal-cer and CCR5, but unlike some cell lines, they do not express CXCR4; in consequence, they permit transcytosis only of HIV isolates capable of interaction with CCR5 [45]. Such R5 strains are those associated with early infection. CCR5-dependent transcytosis and presentation to subepithelial T cells could act as a filter, accounting for the limited transmission of CXCR4dependent isolates from chronically infected patients. Aside from their importance for HIV pathogenesis, these results suggest that M-cell interactions with other viruses may be highly specific; the receptor interactions necessary for uptake by M cells will be of obvious interest. Within the vagina, DCs may be susceptible to direct infection by lumenal virus. In one report, infection of CD4þ T-cells, but not of DCs, was observed three days after intravaginal delivery of SIV to macaques [46]; however, other investigators found that DCs became infected within hours of vaginal exposure, and then migrated rapidly to regional lymph nodes [47]. Intraepithelial Langerhans cells appeared to be infected first [47]; subepithelial DCs expressing the alternative receptor DCSIGN [48] are likely to be involved in the spread of infection to other lymphoid cells.
Conclusions As demonstrated by the HIV studies, viruses may cross mucosal barriers by a variety of mechanisms. Transmission of HIV in humans is likely to involve several of these, with some more important at particular anatomic sites; alternatively, some of the reported mechanisms may operate only in experimental systems. Understanding of how viruses actually infect will require new information about the molecular mechanisms of attachment and entry. Even more important will be detailed information about precisely what cell types and tissues are infected in vivo. Current Opinion in Microbiology 2003, 6:386–391
Acknowledgements My work on virus interactions with polarized epithelium has been supported by the NIH, the Cystic Fibrosis Foundation and the American Heart Association. I thank Susan Coffin for her comments. I apologize to any investigators whose work I have omitted or inadvertently misunderstood.
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