Living in the liver: hepatic infections

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1 Living in the liver: hepatic infections Ulrike Protzer 1, Mala K. Maini 2 and Percy A. Knolle 3 Abstract The liver has vital metabolic and clearance functions that involve the uptake of nutrients, waste products and pathogens from the blood. In addition, its unique immunoregulatory functions mediated by local expression of co-inhibitory receptors and immunosuppressive mediators help to prevent inadvertent organ damage. However, these tolerogenic properties render the liver an attractive target site for pathogens. Although most pathogens that reach the liver via the blood are eliminated or controlled by local innate and adaptive immune responses, some pathogens (such as hepatitis viruses) can escape immune control and persist in hepatocytes, causing substantial morbidity and mortality worldwide. Here, we review our current knowledge of the mechanisms of liver targeting by pathogens and describe the interplay between pathogens and host factors that promote pathogen elimination and maintain organ integrity or that allow pathogen persistence. Liver sinusoidal endothelial cells (LSECs). Cells that line the hepatic sinusoids and take up molecules from the blood. LSECs function as liver-resident antigen-presenting cells and contribute to the induction of local tolerance. 1 Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich, Germany. 2 Division of Infection and Immunity, University College London, London WC1E 6JF, UK. 3 Institutes of Molecular Medicine and Experimental Immunology, Friedrich- Wilhelms-Universität Bonn, D Bonn, Germany. s: protzer@tum.de; m.maini@ucl.ac.uk; percy.knolle@ukb.uni-bonn.de doi: /nri3169 The liver is a vital organ that fulfils diverse but closely connected functions in the metabolism of carbohydrates, proteins and lipids, the clearance of toxins and pathogens, and the regulation of immune responses. Lipids, peptides, carbohydrates and nutrients (such as iron) are transported to the liver through gut-derived portal venous blood, and then pass through sinusoidal lining cells before finally being taken up and metabolized by hepatocytes. As immune responses against antigens that are metabolized in the liver could cause local organ damage, such responses are regulated in a unique manner in the liver. The liver microenvironment induces immune tolerance towards antigens that are taken up and presented (or crosspresented) by tolerogenic non-parenchymal liver cells or expressed by hepatocytes and directly presented on MHC molecules 1. This combination of organ-specific immunobiology and physiological roles in metabolism and toxin removal predisposes the liver to infection by pathogens that circulate in the blood and exploit these functions. Indeed, several clinically important pathogens specifically target the liver and establish chronic infections in hepatocytes. Targeting of the liver, followed by the presentation of microbial antigens in the liver rather than in lymphoid tissues, may allow pathogens to escape mediated immunity and to establish hepatic infection. Although most infectious microorganisms that reach the liver via the blood are rapidly cleared, it is evident from the success of certain pathogens such as the hepatitis B and hepatitis C viruses and malaria-causing Plasmodium spp. (BOX 1) in establishing hepatic infections that the liver provides a favourable environment for escaping immune responses. Here, we review our current knowledge on the cellular and molecular mechanisms that allow pathogens to reach the liver and establish chronic infections in hepatocytes. Liver targeting by pathogens The liver clears blood-borne pathogens through uptake by hepatic scavenger cells, such as liver sinusoidal endothelial cells (LSECs) and Kupffer cells. Despite intensive efforts, liver-specific or hepatocyte-specific receptor molecules that mediate pathogen binding have not been identified. Instead, hepatotropic pathogens attach to and are taken up by hepatocytes following binding to broadly expressed molecules, suggesting that hepatotropism results from functional properties of the liver rather than from the expression of unique receptor molecules. These properties may involve the physio logical processes that transport essential nutrients across sinusoidal cells to hepatocytes or a particular cellular milieu that provides hepatocyte-specific transcription and replication factors. Hepatocytes are shielded from the bloodstream, and therefore from blood-borne pathogens, by Kupffer cells, LSECs and hepatic stellate cells (FIG. 1). Electron microscopy studies indicate that fenestrae (small openings) in LSECs can be up to 100 nm in diameter. However, the passage of gold particles larger than 20 nm was found to be prevented by the presence of electron-lucent material, such as extracellular matrix 2, suggesting that passive diffusion of pathogens into the space of Dissé is unlikely. However, this sinusoidal barrier can be overcome either by the mechanical force generated by NATURE REVIEWS IMMUNOLOGY VOLUME 12 MARCH

2 Box 1 Clinically relevant pathogens that target the liver The liver is targeted by several important human pathogens. Plasmodium spp. cause malaria in humans and are transmitted by Anopheles spp. mosquitoes. Plasmodium spp. sporozoites are transmitted from the saliva of a biting female mosquito. Most sporozoites migrate to the liver and invade hepatocytes following migration through Kupffer cells. During the hepatic stage, sporozoites mature into schizonts that contain many merozoites. The parasites bud from hepatocytes in a vesicular form called merosomes, which protect the merozoites from immune recognition before they infect erythocytes. Asexual merozoites spread between erythrocytes before developing into female and male gametocytes, the sexual form of the parasite, which are then taken up again by female mosquitoes during subsequent bites. Hepatitis A virus (HAV) and hepatitis E virus (HEV) belong to different virus families and have marked differences. HAV and HEV are non-enveloped viruses with a plus-strand RNA genome. They are transmitted via the faecal oral route and do not establish chronic infections. Whereas HAV infects only humans, HEV also infects animals. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are human blood-borne viruses. HBV is a small, enveloped DNA virus that deposits a covalently closed circular DNA genome in the nucleus to persist in the host. HBV is transmitted by sexual contact, by direct blood contact and at birth from mother to child. HCV is an enveloped virus with a plus-strand RNA genome. It is transmitted by direct blood blood contact. Hepatitis D virus (HDV) is a satellite virus that packages its RNA genome into the envelope of HBV and therefore coexists with and follows the infection pathway of HBV. HBV persists in >90% of infected neonates, but it is cleared in >90% of adults. HCV persists in 50 80% of all infected individuals. The high numbers of chronic carriers (350 million for HBV and 170 million for HCV worldwide) account for the rapid increase in the incidence of hepatocellular carcinoma. Kupffer cells Specialized macrophages in the liver that line the sinusoidal vessels. They present antigens, regulate local immune responses and remove microbial particles, endotoxins and other noxious substances that are present in portal venous blood. Hepatic stellate cells A perisinusoidal cell population within the space of Dissé that controls sinusoidal diameter and hepatic blood flow. Stellate cells are the main reservoir of retinol in the liver and contribute to the development of liver fibrosis following inflammation. They have antigen-presenting cell function and contribute to local hepatic immune tolerance. Space of Dissé The space between liver sinusoidal endothelial cells (LSECs) and hepatocytes that is filled with extracellular matrix and is populated by hepatic stellate cells. Access to the space of Dissé is provided through fenestrae in LSECs or following transcytotic transport through LSECs. cells flowing through sinusoids, which has been shown to allow chylomicrons (lipoprotein particles that are 100 nm in diameter and flexible) to squeeze through endothelial cell fenestrae 3, or by active transport across sinusoidal cells, as has been reported for the delivery of iron to hepatocytes by transferrin 4. Similar active transport processes may explain how gold particles that are larger than 20 nm and coated with ligands for the mannose receptor (a C type lectin expressed by sinusoidal cells) can access hepatocytes 2. Indeed, active transport processes are known to be important for the directed delivery of IgA across mucosal cells and of chemokines across endothelial cells 5,6. Given that LSECs and Kupffer cells have extensive receptor-mediated endocytic capacity 7, it is likely that transcytosis is more important in liver physiology than is currently appreciated. So, circulating pathogens might infect hepatocytes either directly by squeezing through LSEC fenestrae or following passage through sinusoidal cells (FIG. 1). These pathways are difficult to distinguish experimentally and may function in parallel, but evidence is accumulating that pathogens use the transport properties of sinusoidal cells to increase the efficiency of hepatocyte infection. Plasmodium spp. initially target Kupffer cells before infecting hepatocytes. Infection by Plasmodium spp. sporozoites has been intensively studied thanks to the availability of well-characterized animal models. Following the delivery of parasites into the skin by a mosquito bite, the rapid migration of sporozoites allows them to escape clearance by phagocytic cells and to enter lymphatics and blood vessels. Once in the circulation, sporozoites rapidly reach the liver and, after gliding on heparan sulphate proteoglycans (HSPGs) in liver sinusoids, they use circumsporozoite protein (CSP) and thrombospondin-related anonymous protein (TRAP) to bind to Kupffer cells 8. Interaction with and passage through Kupffer cells is important for hepatocyte infection 9,10, indicating that the parasite uses Kupffer cells to overcome the sinusoidal barrier and, ultimately, to infect hepatocytes 11. The switch between continued migration and infection is determined by the high level of sulphation of HSPGs that are found on hepatocytes, which promotes proteolytic cleavage of CSP and initiates signalling events in the parasite that promote infection 12. The expression of CD81 by hepatocytes is also required for infection by Plasmodium falciparum and Plasmodium yoelii 13. Once inside a hepatocyte, the parasites develop into merozoites, which are released into the sinusoid following hepatocyte rupture and are then able to infect erythrocytes 14. Taken together, these data show that sporozoites not only use their migratory capacity to escape elimination by phagocytic cells, but also use Kupffer cells to increase their efficiency at infecting hepatocytes. Liver infection by hepatitis C virus. Compared with parasite infection, infection by hepatotropic viruses involves different processes, as viruses cannot actively move. Moreover, our understanding of how hepatotropic viruses target the liver in vivo is much less detailed, owing to the lack of well-characterized smallanimal models. New hepatitis C virus (HCV) particles are released from an infected cell as lipoviroparticles 15, which are formed by the binding of the HCV envelope proteins E1 and E2 to host cell lipoproteins. The circulation of lipoviroparticles and their ability to mediate infection implies that lipid transport pathways may be involved in liver targeting by HCV. Furthermore, E2 binds to the C type lectins DC specific ICAM3 grabbing non-integrin (DC-SIGN), which is expressed by dendritic cells (DCs) and Kupffer cells, and liverand lymph node specific ICAM3 grabbing nonintegrin (L SIGN), which is expressed by LSECs 16,17. C type lectins trap HCV on sinusoidal cells in the liver 18,19, but it remains unclear whether the fate of this trapped HCV is lysosomal degradation or infection of hepatocytes in trans. Although there is no evidence for the occurrence of HCV trans-infection in vivo, HIV is known to use DC SIGN to facilitate its transport by DCs to lymphatic tissue, where it can then infect CD4 + s in trans 20. The receptors involved in HCV uptake into hepatocytes have been identified using cultured hepatoma cell lines. In a coordinated multistep process, HCV attaches to HSPGs, binds to the low-density lipoprotein (LDL) receptor, scavenger receptor B1 and CD81 on the hepatocyte surface, and then binds to claudin 1 and occludin in tight junctions before being endocytosed The epidermal growth factor receptor (EGFR) and ephrin type A receptor 2 (EPHA2) were the most recent additions to the list of host factors that are involved in HCV infection 26. None of these receptors, however, is expressed exclusively by hepatocytes, and it remains unclear how liver targeting by HCV is achieved. 202 MARCH 2012 VOLUME 12

3 Hepatocyte LSEC Stellate cell Microvillus Space of Dissé d Hepatic sinusoid TLR Virus RIG-I b RIG-I Sporozoite c Kupffer cell Parasitophorous vacuole a Endosome TLR3 RIG-I IRF3 IPS1 IFN response Figure 1 Liver microanatomy. Sinusoidal cell populations (Kupffer cells, liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells) form a loose physical barrier between hepatocytes and the blood circulating within the sinusoids. Hepatocyte microvilli make contact with sinusoidal cells and protrude through endothelial cell fenestrae into the sinusoid lumen. Blood-borne pathogens may infect hepatocytes through direct contact with hepatocytes, either after passage through fenestrae (a) or by contacting microvilli that extend into the sinusoidal lumen (b). Pathogens may also first exit the bloodstream by entering Kupffer cells (c) or LSECs (d) before infecting their final target cell, the hepatocyte. Pathogens may escape innate immune sensing by Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) both in sinusoidal cell populations and after infecting hepatocytes. For example, malarial Plasmodium spp. sporozoites evade immune sensing by remaining in a parasitophorous vacuole, and hepatitis C virus escapes cytosolic recognition by helicases by blocking the signalling molecule IFNB-promoter stimulator 1 (IPS1). IFN, interferon; IRF3, IFN-regulatory factor 3. Liver infection by hepatitis B virus. Also for hepatitis B virus (HBV), no hepatocyte-specific receptor has been identified, although cell culture-based HBV infection systems have mapped important determinants of HBV entry 27. Myristoylation and the amino terminal 77 amino acids of the large HBV envelope protein 28 and the antigenic loop of the small HBV envelope protein 29 are crucial for the infectivity of the virus 30. The attachment of HBV to hepatocytes requires interactions with highly sulphated HSPG 31, but additional receptor mol ecules remain unknown. Interestingly, a very low number of HBV particles (<10) is sufficient to establish hepatocyte infection in vivo 32,33, indicating that liver targeting by HBV is extremely efficient. This may be enabled by initial scavenging of the virus by LSECs, as described for duck HBV 34, or by other sinusoidal cells. The apparent contradiction between high efficiency in liver targeting and rather inefficient uptake of virus by cultured hepato cytes 27,31,33 might be explained by transcytosis of the virus across sinusoidal cells 34. Liver infection by hepatitis A and hepatitis E viruses. Hepatitis A virus (HAV) and hepatitis E virus (HEV) are food-borne pathogens that traverse gut epithelial cells to reach the blood and then the liver. The putative attachment receptor for HAV is a mucin-like class I integral-membrane glycoprotein that is ubiquitously expressed 35 37, and HAV can replicate in different cell types in vitro. However, in vivo, the replication of HAV does not seem to occur outside the liver. It has been proposed that HAV targets the liver through a physiological transport pathway, such as the enterohepatic circulation of IgA. In this model, HAV-specific IgA antibodies produced in the intestinal mucosa bind to circulating HAV and serve as carriers of the virus. Kupffer cells express the Fcα receptor 38 and thus may bind to the IgA HAV complexes and transfer them to hepatocytes, where the virus can be taken up via the asialoglycoprotein receptor. However, the in vivo relevance of this process is not clear, because IgA HAV complexes may be eliminated before reaching the hepatocytes. NATURE REVIEWS IMMUNOLOGY VOLUME 12 MARCH

4 Granulomas Structures that are orchestrated by macrophages at different stages of activation and are usually surrounded by a layer of lymphocytes. These macrophages resemble epithelial cells and often include multinucleated giant cells. Granuloma formation is a chronic inflammatory response that can be initiated by various infectious and non-infectious agents. Pattern-recognition receptors Immune sensory receptors such as membrane-bound Toll-like receptors or cytosolic RIG-I-like helicases that recognize conserved structures of pathogens. LPS tolerance A state of hyporesponsiveness to various pro-inflammatory stimuli that results from continuous exposure to low-level lipopolysaccharide derived from the gut. It was described first for Kupffer cells. Unfolded protein response A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins and causes cell cycle arrest and apoptosis. Autophagy An evolutionarily conserved process, in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation and recycling, through fusion with lysosomes. Liver infection by bacteria. Hepatotropism of bacteria has not been described, and most bacteria that reach the liver through the blood are efficiently cleared by immune cells. However, some bacteria, such as mycobacteria and Listeria spp., can establish granulomas in various tissues, including the liver 39,40. Granuloma formation by mycobacteria is driven by infected macrophages, which secrete bacterial proteins that induce the expression of matrix metalloproteinase 9 (REF. 41), leading to tissue remodelling, which is required for the generation of granulomas 42. These granulomas can wall off infecting bacteria from non-infected surrounding tissue 39, but they have also been shown to contribute to the dissemination of virulent bacteria 43. Therefore, although rarely observed, it is possible that granulomas provide a distinct anatomical compartment in the liver that supports the survival of bacteria. Innate defence in the liver and pathogen evasion Hepatic innate immune defence. The initiation of immune responses against infecting pathogens requires the detection of pathogens by patternrecognition receptors (PRRs). Importantly, Toll-like receptors (TLRs) and cytosolic helicases (such as retinoic acid-inducible gene I (RIG I) and melanoma differentiation-associated gene 5 (MDA5)) are expressed not only by bone marrow-derived immune cells, such as Kupffer cells and hepatic DCs, but also by liver-resident cells, such as hepatocytes, LSECs and hepatic stellate cells Small differences in PRR expression between hepatic and splenic immune cells have been documented 49, but both cell populations are able to sense pathogens 50. Kupffer cells and LSECs can detect low concentrations of TLR ligands and produce interleukin 6 (IL 6) and type I interferons (IFNs) 46,52. IL 6 induces the expression of innate effector molecules such as the acutephase protein C reactive protein by hepatocytes 51, and type I IFNs have potent antiviral effects, increase natural killer (NK) cell activity and improve antigen presentation. However, the constant exposure of liver cells to the TLR ligand lipopolysaccharide (LPS), which is present in portal venous blood, causes a state of hyporesponsiveness (known as LPS tolerance) towards further pro-inflammatory immune stimulation 53. Thus, LSECs and hepatic DCs do not mature into immunogenic antigen-presenting cells (APCs) 46,54, and this may impair the local induction of cytotoxic T lymphocyte (CTL) responses 55. It is possible that this limits pathogen-specific defence, but no evidence for this idea has been reported. Other innate immune cells, such as NK cells, are greatly enriched in the liver compared with the circulation and may contribute to viral defence. This is supported by the finding that certain killer cell immunoglobulin-like receptor (KIR) haplotypes are associated with the resolution of acute HCV infection 56. Moreover, natural killer T (NKT) cells contribute to antibacterial defence 57, and non-classical innate immune cell populations (such as γδ s) may also support hepatic immune defence following infection. Immune evasion strategies of pathogens in the liver. Pathogens that target the liver seem to actively avoid or even overcome local immune sensing. This is important at two stages: first, during entry into the liver; and, second, during productive hepatocyte infection. For example, HBV and HCV capsids are recognized by TLR2, which is expressed by macrophages and Kupffer cells 58,59. However, the activation of PRRs by HBV leads to the release of pro-inflammatory cytokines and IL 10, but not type I IFNs, from Kupffer cells and LSECs 60. Accordingly, patients with acute HBV infections have high plasma levels of IL 6 and IL 10, which have been shown to exert tissue-protective and immunoregulatory effects 61,62, but no increase in antiviral type I IFNs 63. This suggests that HBV and HCV may sneak under the immune radar not only by using a limited number of virus particles to efficiently target the liver, but also by avoiding the induction of antiviral IFNs and by initiating cytokine responses that confer tissue protection. Once an infection is established, pathogens can escape innate immune recognition by adapting their life cycles. For example, HBV is considered to be a stealth virus, as it escapes immune sensing by synthesizing its genome within the viral capsid 64. In addition, HBV gene products suppress the response of liver cells to TLR ligands 45,60. HAV and HCV have similar genome structures and share many aspects of their replication strategies. Moreover, both viruses actively interfere with immune sensing 65,66. HCV expresses one polyprotein precursor, which activates an unfolded protein response and induces autophagy in the host cell, and this promotes HCV RNA replication and suppresses the induction of type I IFN responses 67. Both viruses replicate via a double-stranded RNA intermediate, which is recognized by endosomal TLR3 and the cytosolic immune sensors RIG I and MDA5 in infected hepatocytes 47,68. The HCV protease NS3 NS4A counteracts RIG I, MDA5 and TLR3 signalling by cleaving the essential mitochondrial signalling molecule IFNB-promoter stimulator 1 (IPS1; also known as MAVS) 69,70 and TIRdomain-containing adaptor protein inducing IFNβ (TRIF), thereby disrupting downstream signalling through IFN-regulatory factor 3 (IRF3) 69,71. Similarly to HCV, HAV can disrupt the RIG I, MDA5 and TLR3 signalling pathways by cleaving IPS1 and TRIF using two distinct precursors of the HAV protease 72,73. However, in chimpanzees, HCV (but not HAV) induces a strong IFN response in the liver 74. This may be explained by the finding that the expression of HCV NS3 NS4A in mice is not sufficient to hinder the induction of type I IFNs or the expression of IFN-responsive genes 75, and it suggests that HCV does not interfere with innate immune sensing as successfully as HAV. Finally, another evasion strategy is used by Plasmodium spp. sporozoites: they establish a parasitophorous vacuole in Kupffer cells that prevents sporozoite surface molecules from being directly recognized by membrane-bound PRRs 8. Sporozoites also inhibit the respiratory burst in Kupffer cells 76. Nevertheless, hepatocytes that have been damaged or die following sporozoite 204 MARCH 2012 VOLUME 12

5 transfer can trigger innate immune responses 77 and, during the erythrocytic phase of infection, parasite-derived glycosylphosphatidylinositol triggers the activation of immune cells through TLR2- and myeloid differentiation primary-response protein 88 (MYD88)-dependent signalling 78. Taken together, these findings suggest that hepatic immune sensing is functional but that certain pathogens have evolved inhibitory and evasion mechanisms to circumvent productive immune responses in liver cells. Clearance of pathogens from the liver Bacteria. Blood-borne bacteria are normally cleared rapidly from the liver by phagocytic hepatic immune cells (FIG. 2a). After ingesting bacteria (such as Borrelia spp.), Kupffer cells attract NKs in a CXC-chemokine receptor 3 (CXCR3)-dependent manner and present bacterial glycolipid antigens on CD1 molecules to NKs 57. The concerted action of these sinusoidal immune cell populations induces an intravascular immune response that prevents further bacterial infection 57. Rapid initiation of immune defence against circulating pathogens within the hepatic sinusoids strengthens the notion that early pathogen sensing supports successful elimination. NKs may be instrumental in this respect, as they can recognize microbial antigens and rapidly exert immune effector functions, thus bridging innate and adaptive immunity 79,80. It is likely that, in addition to NKs, the sizeable hepatic populations of effector memory s and NK cells may participate in rapid local or even systemic induction of immune defence Thus, our knowledge of successful antibacterial defence in the liver indicates a functional distinction between the hepatic sinusoidal compartment, where pathogen recognition by immune cells can eliminate pathogens and prevent them from accessing hepatocytes, and the parenchymal compartment, where infection is more difficult to eradicate and may even be facilitated through the tolerogenic properties of the local microenvironment and organ-resident cell populations. Malaria parasites. Infection by Plasmodium spp. provides an example in which the pathogen is able to overcome the barrier and effector mechanisms of sinusoidal cells to infect hepatocytes. However, Plasmodium spp. sporozoites normally do not persist in the liver, as only their initial maturation and replication stages require hepatocytes and they then actively egress from the liver as merozoites to initiate blood-stage infection 85. Natural exposure during repetitive infection with sporozoites in areas endemic for malaria often fails to generate protective immune responses, which are characterized by CTL and antibody responses specific for parasite CSP 86. The priming of parasite-specific CTLs occurs in lymph nodes that drain the site of skin inoculation with a Bacteria Hepatic sinusoid IL-1β IFNs CXCL9 TCR CD1d CXCR3 NKT cell NK activation IFNγ b IL-6 Induction of adaptive immunity Dendritic cell IFNs P2X7 LSEC Kupffer cell CD95L CD95 TNF ATP Virus Healthy hepatocyte Infected dying hepatocyte Figure 2 Host mechanisms involved in the clearance of pathogens in the liver. a Scavenger sinusoidal cell populations, such as Kupffer cells, phagocytose circulating bacteria and crosstalk with natural killer T (NKT) cells to generate strong intravascular pathogen-specific immune responses. Inhibiting the access of pathogens to hepatocytes may have an important role in preventing the development of persistent hepatic infections. b The death of infected hepatocytes during viral replication may cause the activation of Kupffer cells or dendritic cells (DCs), which in turn promote the killing of other hepatocytes through CD95 (also known as FAS) and the release of pro-inflammatory mediators. Material from dying virus-infected cells increases cross-priming by DCs and thereby augments pathogen-specific adaptive immunity 98,175. Combinatorial stimulation by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), such as ATP, may allow immune-mediated control of established hepatic infections. CXCL9, CXC-chemokine ligand 9; CXCR3, CXC-chemokine receptor 3; IFN, interferon; IL, interleukin; LSEC, liver sinusoidal endothelial cell; TCR, receptor; TNF, tumour necrosis factor. NATURE REVIEWS IMMUNOLOGY VOLUME 12 MARCH

6 Damage-associated molecular pattern (DAMP). A molecule that is produced by or released from host cells following cellular stress, damage or non-physiological cell death. DAMPs are thought to be responsible for the initiation and perpetuation of inflammatory responses and tissue repair under non-infectious conditions. Examples include: hyaluronan (which is released from the degraded stroma); HMGB1 (which is released from the nucleus); and ATP, uric acid, S100 calcium-binding proteins and heat-shock proteins (which are released from the cytosol). They can induce tolerogenic or immunogenic myeloid dendritic cells, depending on the nature of other signals that are present. Pathogen-associated molecular pattern (PAMP). A conserved microbial structure that is not found in mammalian cells and is recognized by non-variable pattern-recognition receptors. PAMPs include microbial components such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin, double-stranded RNA and other cytosolic nucleic acids. sporozoites, but not in the liver 86,87, and requires CD4 + T helper cells that produce IL 4 (REF. 88). CSP-specific CTLs that express the IL 4 receptor and receive IL 4 signals differentiate into effector memory CTLs that home to the liver to provide protection against sporozoite infection, whereas CTLs primed in the absence of CD4 + -mediated help fail to do so 89,90. These results reveal that even those CTLs that are primed by professional APCs fail to protect against liver infection unless they reside in high numbers in the liver 85. It can be assumed, given the low numbers of sporozoites and the short time frame between hepatocyte infection and the release of merozoites, that protection would require high numbers of CTLs to rapidly find and kill the few infected hepatocytes. Key to such escape from hepatic CTLs may therefore be efficient liver targeting and hepatocyte infection in combination with the amplification step, as sparse sporozoite-infected hepatocytes are sufficient to initiate blood-stage infection. The unique microarchitecture of the liver probably assists the escape of the few infected hepatocytes from CSP-specific CTLs, because the extensive hepatic sinusoidal meshwork with irregular blood flow acts like a maze in which CTLs are randomly dispersed. As there is autoregulation of the size of the CSP-specific clonal population through CTL-mediated elimination of APCs presenting CSP, only a sufficiently high antigen concentration can generate protective numbers of CSPspecific CTLs 90. As predicted from this assumption, vaccination with high numbers of irradiated sporozoites or genetically modified replication-defective sporozoites and very frequent exposure to sporozoites, leading to prolonged antigen presentation, procures protection 91,92. Viruses. In contrast to Plasmodium spp., hepatitis viruses remain in hepatocytes; their elimination requires the induction of strong adaptive immune responses, which depend on appropriate innate immune stimuli. However, the molecular mechanisms underlying selflimited versus long-term, persistent viral infection of the liver cannot be clearly distinguished. Comparison of HAV and HCV infection may shed light on this issue. As noted above, HAV and HCV both have strategies that allow them to circumvent the induction of type I IFN responses 74. However, HAV and HCV infections have different outcomes. HAV never causes chronic hepatitis, although it persists for many weeks in the livers of infected chimpanzees even after clearance of the virus from the serum or faeces 74. HCV induces stronger IFN responses and either is cleared more rapidly than HAV 74 or establishes a persistent infection in the liver. Although early and strong innate immune responses in HCV-infected individuals are an indicator of subsequent clearance of the infection from the liver 93, immune responses fail to clear HCV infection in more than 50 percent of cases. It is possible that the difference in clinical outcomes lies in the unique properties of HAV. In contrast to HCV, HAV is a non-enveloped virus that requires the disruption of host cell membranes to release its progeny. This may provide a distinct immune stimulatory signal, such as a damage-associated molecular pattern (DAMP), that can overcome viral immune escape and liverintrinsic tolerogenic mechanisms. Support for this assumption comes from the observation that Kupffer cell activation by dying hepatocytes provides a synergistic signal to pathogen-associated molecular pattern (PAMP)-driven immune activation and promotes hepatic inflammation 94 (FIG. 2b). Although hepatic inflammation induces the recruitment of neutrophils, which increase local inflammation 95, and the production by innate immune cells of type I IFNs, which contribute to the control of hepatic viral infection 52,96, the elimination of hepatocellular viral infections requires s. The uptake of antigens derived from apoptotic virus-infected cells by DCs through the endocytic receptor C-type lectin 9A (CLEC9A) increases the functional maturation of those DCs and the efficiency of cross-priming 97,98. However, more efforts to identify receptors for DAMPs will be required to unravel the immune-sensing mechanisms that determine the successful induction of strong responses and the elimination of viral infection from hepatocytes. HBV and HCV, despite being important examples of persistent hepatic infections, can also be spontaneously controlled following acute infection. Following the resolution of acute infection, HCV is eliminated by almost all patients 99, whereas HBV is controlled but not completely eliminated, and may reactivate under strong immunosuppression 100. The initiation of immune responses and the resolution of infection are protracted in HAV, HBV or HCV infections compared with other acute viral infections 101. This suggests the occurrence of early viral evasion of immune sensing and immune control that can be successfully overcome in the first few months after infection. Animal models and human studies of acute resolving infections have highlighted the importance of vigorous and multi-specific CTL responses, which develop in the presence of adequate help derived cytokines (such as tumour necrosis factor and IFNγ) limit viral replication in hepatocytes, which ensures an initial reduction in viraemia without significant liver damage 103, and CTL-mediated cytotoxicity is required for infection control. Long-term persistence of infection If HBV and HCV escape immune-mediated clearance during acute infection, they can live in the liver for many years without inducing disease or they can provoke immune-mediated organ damage that culminates in liver cirrhosis and hepatocellular carcinoma. Treatment with type I IFNs at later stages, when infection has become chronic, is much less efficient than during acute infection. This suggests that distinct mechanisms prevent virus elimination in chronic and acute infection and that the induction of virus-specific immune responses must occur rapidly to prevent viral persistence. The correlates of immune control in the setting of chronic infection, however, are poorly understood. 206 MARCH 2012 VOLUME 12

7 Suicidal emperipolesis A recently described process during which s invade hepatocytes, leading to death. Evasion of humoral immune responses. Neutralizing antibodies contribute to the immune control of viral infections and to long-lasting protection. The importance of B cell responses in the control of HBV infection has been highlighted recently by the occurrence of disease reactivation induced by the B cell-depleting drug rituximab (Rituxan/MabThera; Biogen Idec/Genentech/ Roche) 104. However, in individuals with chronic HBV infection, the large amounts of secreted HBV surface antigen (HBsAg) that are present in excess of the levels of infectious virus can capture and saturate circulating HBV-specific antibodies, preventing them from neutralizing the virus. Moreover, in chronic HCV infection, the virus continuously evades neutralizing antibodies owing to the selection of escape variants 105. In addition, viruses escape neutralizing antibodies by creeping directly from one hepatocyte to another 106. Depletion and exhaustion of virus-specific CTLs. The most obvious immune deficiency in chronic HBV or HCV infection is the depletion of virus-specific CTLs or their functional inactivation. depletion is partially attributable to the enhanced susceptibility of these cells to apoptosis 107,108. This apoptotic propensity may be imposed by tolerogenic hepatic priming 109, which induces death through BCL 2 interacting mediator of cell death (BIM) 110. BIM is a key pro-apoptotic mediator that contributes to the attrition of virusspecific CTLs during HBV and HCV infection 107,111,112. BIM-mediated apoptosis may be promoted by coinhibitory signals through cytotoxic T lymphocyte antigen 4 (CTLA4) or by -intrinsic transforming growth factor β (TGFβ) 111,113. Suicidal emperipolesis a recently described phenomenon whereby CTLs that recognize their cognate antigen in the liver invade hepatocytes for subsequent degradation 114 may also contribute to attrition. The few remaining virus-specific CTLs in chronic infection have functional defects, in keeping with the hierarchical loss of effector functions, termed exhaustion, that has been described for high-dose persistent viral infections 115. A main cause of exhaustion is an excess of co-inhibitory signals that outweighs the co-stimulatory signals and results in functional inhibition of s. This is best defined for programmed cell death protein 1 (PD1), a co-inhibitory molecule that tightly regulates reactivity to prevent autoimmunity More recent work has revealed that multiple layers of negative co-regulation contribute to exhaustion in chronic infection 119. This is supported by studies of HBV and HCV that have shown nonredundant roles for other co-inhibitory molecules, such as CLTA4, immunoglobulin domain and mucin domain protein 3 (TIM3; also known as HAVCR2) and 2B4 (REFS 111,120,121). HCV- and HBV-specific CTLs are enriched in the livers of chronically infected patients 122,123 and express higher levels of co-inhibitory receptors than their circulating counterparts 120,121. The high antigen load in HBV and HCV infection may be an important factor that promotes co-inhibitory receptor expression by virus-specific CTLs. Consistent with this idea, when CTLs are unable to recognize their cognate antigen because of viral epitope mutations, the expression of co-inhibitory receptors is downregulated 124. However, antigen load is not the only determinant of PD1 expression by intrahepatic s, as expression levels remain high on virus-specific CTLs that reside in the liver after virus titres in the blood have decreased 125. The contribution of co-inhibitory pathways to intrahepatic tolerance is further promoted by the high levels of ligands for the co-inhibitory molecules expressed in the liver. Kupffer cells, LSECs, stellate cells and hepatocytes all express PD1 ligand 1 (PDL1) 116, , and PDL1 expression levels are upregulated in patients with viral hepatitis compared with controls 129,130. Kupffer cells also express galectin 9, which is the ligand for TIM3, and its expression is similarly upregulated in HCV infection 131. Thus, co-inhibitory pathways that operate to mitigate overzealous responses in the liver 117,132 may be induced inappropriately by viruses to subvert effective antiviral immunity. CTL exhaustion is exacerbated by a lack of adequate CD4 + help 115, a situation that is likely to be relevant in the liver, where CD4 + s are greatly outnumbered by CTLs 133 and where non-professional APCs prime s in the absence of CD4 + help 134. The paucity of CD4 + help observed in the liver in the steady state is accentuated in chronic infection, during which the CD4 + compartment is likely to be affected by inhibitory mechanisms similar to those that affect CTLs 135. Compared with normal livers, the livers of patients with HBV or HCV infection contain increased numbers of forkhead box P3 (FOXP3)-expressing CD4 + regulatory T (T Reg ) cells, which may contribute to the extrinsic regulation of effector s 136,137. However, these T Reg cells also upregulate PD1 expression in HCV-infected livers and are thereby subjected to the constraining effects of PDL1 through inhibition of the phosphorylation of signal transducer and activator of transcription 5 (STAT5) 137. Intrahepatic expression of soluble immunosuppressive factors. In addition to the impaired function caused by membrane-bound inhibitory molecules, other factors of the hepatic milieu can regulate local immune effector functions. The liver is a rich source of immunoregulatory cytokines, such as IL 10 (REF. 138), which impedes the function of virus-specific s and may act synergistically with PD1 (REF. 139). IL 10 production is induced in acute and chronic HBV infection 63,140 and can suppress virus-specific s in the HCV-infected liver 141. HBV- and HCV-specific CTLs are themselves capable of IL 10 production , and can thereby attenuate antiviral immunity in an autocrine feedback loop to prevent excessive immune-mediated liver damage. s may also be deprived of the amino acids arginine and tryptophan in the liver, and this results in the induction of stress response pathways in the s that lead to their proliferative arrest 144,145. Enzymes responsible for the catabolism of these amino acids are released by damaged hepatocytes and other intrahepatic populations and are induced in HBV and HCV infections 146,176. NATURE REVIEWS IMMUNOLOGY VOLUME 12 MARCH

8 Ribavirin A drug that interferes with RNA metabolism and blocks viral replication. Ribavirin is used in combination with interferon α to treat hepatitis C. Intriguingly, many of the same soluble immunosuppressive factors and co-inhibitory molecules can be induced in acute, resolving hepatic infections 63,129, during which they facilitate the contraction of the immune response and limit organ damage while maintaining viral control. By contrast, when these mechanisms become relentlessly activated during persistent infection, they may perpetuate the disarming of the already diminished antiviral immune responses. The role of other immune cells in chronic hepatic infection. Innate immune effector cells may be able to substitute for the paralyzed response in hepatic infections. One good candidate might be NK cells, as they are present in large numbers in the liver 133,147. Recent findings suggest that NK cells with antigen-specific memory for viral infections are selectively maintained in the liver owing to their expression of CXCR6 (REF. 84). However, NK cells are also vulnerable to tolerance mechanisms in the liver. In both HBV and HCV infections, NK cells retain cytotoxic potential 140,147,148, but they fail to produce IFNγ, an effect that may be mediated by IL 10 producing Kupffer cells 140,149,150. In addition, there are large numbers of γδ s and s that express NK cell markers (such as CD56 and CD161) in the liver 81,151 ; whether these populations are subject to similar tolerance mechanisms or contribute to pathogenesis remains unclear. Classical invariant NKs are emerging as potent regulators of hepatic immune responses 80, although they are present in much lower numbers in human HCV-infected livers than in mouse livers 152. Taken together, these findings suggest that chronic viral infection in the liver is perpetuated by the inhibition of virus-specific and NK cell responses through several mechanisms (FIG. 3), which may have evolved to protect the liver from immune-mediated damage. Overcoming persistent viral infection in the liver The combination of immune escape strategies used by HBV and HCV 153, the depletion or exhaustion of CTLs and the tolerogenic hepatic microenvironment that suppresses virus-specific effector functions together contribute to the persistence of HBV and HCV infections (TABLES 1,2). Differences in treatment modalities and outcomes are related to the different viral replication strategies. Current therapies for HCV infection that involve IFNα in combination with ribavirin and novel antiviral drugs 154 can eliminate the virus by preventing viral replication, which is required for HCV persistence. By contrast, antiviral therapy with reverse transcriptase Hepatic sinusoid BIM Galectin 9 TIM3 Kupffer cell IL-10 IDO, TDO NK cell IL-10 PD1 T Reg cell TGFβ BIM NK cell PD1 MDSC PDL1 Arginase DC BIM PD1 LSEC TGFβ Stellate cell PDL1 PDL1 CTLA4 Healthy hepatocyte Virus Infected hepatocyte Suicidal emperipolesis Figure 3 Host mechanisms that promote the persistence of liver infection. There are several layers of immunoregulatory and co-inhibitory signalling processes in the liver. Indoleamine 2,3 dioxygenase (IDO) and arginase are expressed at high levels in the liver and metabolize amino acids that are essential for immune cell proliferation and function, thus attenuating natural killer (NK) cell and immune reactivity. Immunoregulatory cell populations such as regulatory T (T Reg ) cells, interleukin 10 (IL 10)-producing cells and myeloid-derived suppressor cells (MDSCs) prevent local expansion of effector populations and restrict the function of the few NK and s present in the infected liver. Co-inhibitory signalling through the binding of programmed cell death protein 1 (PD1) on s to PD1 ligand 1 (PDL1) on Kupffer cells, liver sinusoidal endothelial cells (LSECs), stellate cells and hepatic dendritic cells (DCs) restricts hepatic immune responses. This inhibition occurs both at the level of priming, by generating anergic or tolerant s, and at the level of the cytotoxic recall response, by limiting the effector function of s in the liver. s that express BCL 2 interacting mediator of cell death (BIM) undergo apoptosis. Suicidal emperipolesis in hepatocytes also contributes to the elimination of s. CTLA4, cytotoxic T lymphocyte antigen 4; TDO, tryptophan 2,3 dioxygenase; TGFβ, transforming growth factor β; TIM3, immunoglobulin domain and mucin domain protein MARCH 2012 VOLUME 12

9 Table 1 Host factors associated with the persistence of viral infection in the liver Host factors Co-inhibitory molecules Immunoregulatory environment Genetic polymorphism Maturity of the immune system Persistent pathogen HBV, HCV HBV, HCV HCV HBV Physiological function Protection of the liver from attack by activated s Local regulation of activity in the liver Advantage for the host not known Adaptation of the newborn s immune system to self Mechanisms promoting viral escape High intrahepatic expression of PDL1 and galectin 9 inhibits the effector function of virus-specific s Local expression of arginase, tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase promotes the depletion of amino acids that are essential for function Single nucleotide polymorphisms in the genes encoding IFNλ or killer cell immunoglobulin-like receptors allow escape from IFNλ activity and protection from NK cell effector function; HLA haplotype may influence escape and hence viral control (for example, HLA B27-restricted responses limit HCV escape) Infection of neonates leads to persistent infection because of their immature immune systems HBV, hepatitis B virus; HCV, hepatitis C virus; IFNλ, interferon λ; NK, natural killer; PDL1, PD1 ligand 1. Refs ,177, IFNλ (Interferon-λ; also known as type III IFNs). There are three IFNλ cytokines, interleukin 28A (IL 28A), IL 28B and IL 29, which can be produced by almost every cell type after infection and bind to a heterodimeric receptor (comprised of the IL 10 receptor β chain and the IL 28 receptor α chain) that is expressed mainly by epithelial cells. They have direct antiviral properties, induce IFN-responsive gene expression and increase antigen presentation. inhibitors controls but does not eliminate HBV, because the covalently closed circular DNA form of HBV DNA remains unaffected 155. The finding that genetic polymorphisms in the IL28B locus correlate with a good response to IFNα treatment of HCV infection provides the rational for developing the IL28B gene product, IFNλ, as an alternative therapy. Moreover, novel approaches are being investigated that combine stimulation of RIG I, to induce type I IFN production in the liver, with the lowering of viral antigen levels by gene silencing 48,159. Finally, immunotherapy approaches could be developed to prevent the attrition of local hepatic -mediated immunity. Such approaches would need to increase both the number and potency of pathogen-specific CTLs and the number of CD4 + T helper cells. To meet these requirements, four different strategies could be envisaged. First, viral antigen levels could be lowered to prevent the exhaustion of virus-specific CTLs. Second, extrahepatic priming could be augmented using a therapeutic vaccine to generate fully functional pathogen-specific CTLs. Third, local regulatory signals that impede effector function and reduce the number of CTLs in the liver could be overridden. And, fourth, functional s that have been redirected to recognize viral antigens could be adoptively transferred. With each of these immunotherapeutic approaches, it is important to appreciate that both cytolytic and non-cytolytic functions of s can contribute to viral control but might also exacerbate liver damage through direct hepatocyte cytotoxicity or by driving inflammatory cell infiltration 160. Accumulating data support the idea that antiviral responses can be boosted without exacerbating the nonspecific lymphocytic infiltrate that causes liver damage 123,147,161,162. This provides the rationale to pursue the development of therapeutic vaccines. Prophylactic vaccination relies on rapid neutralization of the invading pathogen by antibodies, whereas successful therapeutic vaccination depends on the induction of broad and polyfunctional responses against key viral antigens 163. Such polyfunctional responses should involve both cytolytic and non-cytolytic clearance of HBV-infected hepatocytes. To counteract the exhaustion caused by high antigen levels, the induction of s should be preceded by the activation of a humoral immune response that reduces antigen levels and limits virus spread. New vaccine protocols therefore use prime boost strategies, in which an adjuvanted protein primes and induces neutralizing antibody responses and a vector-based vaccine then boosts responses 164. Alternatively, viral antigen levels may be reduced by gene silencing techniques 165,166. Future therapeutic vaccinations may also incorporate, or be combined with, measures that are designed to enhance co-stimulation or override the inhibition of s. However, overriding regulatory signals from the liver microenvironment for example, by blocking coinhibitory molecules such as PD1 may pose a risk of further immunopathology in the liver, as the absence of PDL1 has been shown to cause severe autoimmune liver damage in animal models 116,117,132. Targeting the downstream master transcriptional regulators of exhaustion may be a more subtle approach and might allow for the heterogeneity of non-redundant pathways that function in patients. The observation that two-thirds of HBV-infected patients who receive allogeneic stem cell transplants from individuals with immunity to HBV clear HBV infection 167,168 is encouraging for the development of adoptive cell therapy strategies. -based therapies are a valid alternative for vaccination strategies, as the numbers and effector functions of the transferred s can be defined. Given the paucity of HBV-specific s found in HBVinfected patients, attempts at expanding these populations in vitro to create sufficient numbers for therapy would be challenging. One approach being developed for the reconstitution of virus-specific CTLs involves redirecting the specificity of s towards key HBV epitopes. In principle, this may be achieved by antibody-mediated NATURE REVIEWS IMMUNOLOGY VOLUME 12 MARCH

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