- Email: [email protected]
Suppression of antiviral responses by antibody-dependent enhancement of macrophage infection
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Vol.24 No.4 April 2003
165
Suppression of antiviral responses by antibodydependent enhancement of macrophage infection Andreas Suhrbier and May La Linn Queensland Institute of Medical Research and the Australian Centre for International & Tropical Health & Nutrition, 300 Herston Road, Herston, Queensland 4029, Australia
Antibody-dependent enhancement (ADE) of macrophage and monocyte infection has been demonstrated in vitro for some of the most deadly RNA viruses known. Recent evidence suggests that ADE-mediated ligation of Fc receptors might suppress host-cell antiviral gene expression by promoting early interleukin-10 (IL-10) secretion, resulting in the expression of suppressor-of-cytokine-signalling (SOCS) proteins and a Th2 bias. These findings provide potential new insights into how ADE might enhance viral infections and exacerbate disease. The ability to infect productively macrophages and monocytes and demonstrate antibody-dependent enhancement (ADE) of macrophage and monocyte infection has been shown in vitro for many RNA viruses, several of which cause some of the deadliest diseases known [1] (Table 1). Curiously, although several DNA viruses can also infect these cells (e.g. cytomegalovirus, poxviruses, adenovirus), ADE has not been widely reported for these viruses. ADE is believed to involve enhanced virus uptake by Fcg receptors (FcgR) when the virus is bound by sub- or non-neutralising antibody, resulting in an increase in virus production, viraemia and pathogenesis [1]. However, a clear correlate between ADE in vitro and ADE-mediated immunopathogenesis in vivo has proven elusive. Even for dengue infections, in which the ADE-phenomena is best described, the role of ADE appears to be difficult to distinguish from other factors, such as virus virulence and the genetic predisposition of the host [1].
…a clear correlate between ADE in vitro and ADE-mediated immunopathogenesis in vivo has proven elusive. Recently, Mahalingham and Lidbury reported that ADE of macrophage infection by the alphavirus, Ross River virus (RRV) was able to inhibit lipopolysaccharide (LPS)-induced antiviral gene activation [2]. This observation suggested that, aside from enhancing viral uptake, ADE might suppress the innate antiviral response of the Corresponding author: Andreas Suhrbier ([email protected]). http://treimm.trends.com
host. The principle first-line defence of the host against RNA viruses involves rapid activation of the interferona/b (IFN-a/b) system, and many RNA viruses have developed strategies to inhibit one or more components of this system [3]. A well known strategy used by alphaviruses (and poliovirus) is rapid shutdown of host-cell translation, which prevents expression of antiviral proteins and transcription factors. Although RRV replication was required, translational shutdown did not appear to be responsible for the specific inhibition of antiviral gene activation by RRV ADE [2]. Thus, the important question is whether enhanced virus uptake mediated by ADE simply expedites deployment of some new alphaviral countermeasure against host defences, or whether Fcg receptor (FcgR) signalling by the antibody-complexed virus somehow contributes to suppression of the antiviral response of the host cell. FcgR-mediated anti-inflammatory signalling A well documented source of anti-inflammatory signals derived from FcR ligation is through the inhibitory FcgRIIb, the primary receptor for clearance of immune complexes in vivo, and the target of anti-inflammatory intravenous g-globulin treatment for autoimmune disorders [4]. However, FcgRIIb ligation-dependent inhibition through its immunoreceptor tyrosine-based inhibitory motif (ITIM) appears to be restricted to the inhibition of activation signals from other FcgRs, with no reports suggesting that FcgRIIb ITIM can inhibit LPS or IFN-stimulated pathways. Recently, Gerber and Mosser showed that FcgR ligation inhibited LPS-induced inflammatory cytokine production by macrophages, and illustrated that the inhibitory effect was as a result of early autocrine interleukin-10 (IL-10) secretion [5]. LPS usually induces late IL-10 production as part of a negative feedback cycle. However, LPS given in concert with FcgR ligation resulted in early IL-10 production and suppression of LPS-induced activation [5]. Importantly, Mahalingham and Lidbury found that alphavirus ADE also induced IL-10 expression, suggesting that a crucial consequence of ADE could be the induction of IL-10 promoted by FcgR ligation [2]. Both studies also illustrated that promotion of IL-10 production by FcgR ligation required a second signal, either from LPS [5] or virus replication [2].
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Table 1. Pathogenic viruses of humans for which ADE of macrophages and/or monocyte infection has been reported
a
Virus
Nucleic acid
Family
Genus
Dengue Japanese encephalitis Murry valley encephalitis Yellow Fever West Nile Tick borne encephalitis Ross River HIV Influenza A Respiratory syncytial Lassa Pichinde Rift valley fever Ebola Rabies Polio Coxsackie B3 Herpes Simplex 1
ssRNAa þ sense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA þsense nonenveloped ssRNA þsense nonenveloped dsDNA enveloped
Flaviviridae Flaviviridae Flaviviridae Flaviviridae Flaviviridae Flaviviridae Togaviridae Retroviridae Orthomyxoviridae Paramyxoviridae Arenaviridae Arenaviridae Bunyaviridae Filoviridae Rhabdoviridae Piconaviridae Piconaviridae Herpesviridae
Flavivirus Flavivirus Flavivirus Flavivirus Flavivirus Flavivirus Alphavirus Lentivirus Influenza virus A,B Pneumovirus Arenavirus Arenavirus Phlebovirus Filovirus Lyssavirus Enterovirus Enterovirus Simplex virus
Abbreviations: ADE, antibody dependent enhancement; ds, double stranded; ss, single stranded.
…a crucial consequence of ADE could be the induction of IL-10 promoted by FcgR ligation. IL-10 is recognised as a key cytokine for the downregulation of inflammatory responses and can inhibit LPS activation of macrophages by stimulating the expression of the suppressor-of-cytokine-signalling 3 (SOCS3) [6]. SOCS3 is also responsible for IL-10-mediated repression of IFN-a-induced gene activation in monocytes [7], with SOCS3 (and SOCS1) identified as key inhibitors of IFNmediated antiviral activities [8]. SOCS1 and/or SOCS3 inhibit the Janus kinases (Jaks), and thereby suppress signal transduction by a number of cytokines and receptors, including IL-12, IFN-g and Toll-like receptor 4 (TLR4). Exploiting IL-10 A number of viruses and intracellular bacteria target macrophages and induce IL-10 and/or produce their own IL-10 homologues to dampen the host immune responses, and thereby stall their elimination from the host [9]. Similarly, ADE might facilitate early IL-10 production, enabling the viruses that infect macrophages to benefit from the anti-inflammatory and immunosuppressive environment created by autocrine IL-10 production [2]. There is no consensus regarding which antibody isotype or FcgR class (I, II or III) is most important for ADE; nearly all isotypes and receptors (including the complement receptor) active in one or more systems [1]. The relative efficiencies of the different FcRs in promoting early IL-10 production, and the potential ability of FcgRIIb ligation to inhibit this process, remain to be examined. However, the evidence so far suggests that, like ADE, there is little specificity. Ligation of FcgRs, scavenger and complement receptors, can suppress LPS-mediated macrophage and monocyte activation [5], and immune complexes are also able to inhibit IFN-g-mediated activation of monocytes [10]. Although not relevant for ADE, ligation of FceR (the http://treimm.trends.com
IgE receptor) on monocytes in the presence of IL-4 and granulocyte – macrophage-colony stimulating factor (GM-CSF) also results in IL-10 production [11], and engagement of the mannose receptor on dendritic cells also suppresses their ability to be activated by LPS [12]. These reports suggest that ligation of a number of receptors on cells of the monocyte – macrophage lineage can lead to broad suppressive activities consistent with IL-10-induced SOCS expression.
…ADE might facilitate early IL-10 production, enabling the viruses that infect macrophages to benefit from the anti-inflammatory and immunosuppressive environment created by autocrine IL-10 production. The model for ADE that emerges (Fig. 1) could explain why ADE operates in vitro for so many RNA viruses because inhibition of the IFN-a/b system is likely to promote replication of most RNA viruses. The model raises the question of whether ADE actually increases the uptake of virus or whether IL-10-mediated suppression of antiviral activity is responsible for enhanced virus production. The model might also explain why ADE has not been widely reported for cytomegaloviruses, poxviruses and adenoviruses. The former two viruses produce their own viral IL-10 homologues [9] and adenovirus produces the E1A protein, which blocks transcription of IFN-responsive genes [3]. Overlapping pathways for antiviral and antibacterial responses One might ask why IL-10-mediated suppression of bacterial LPS-activated inflammatory and antiviral responses has any physiological relevance in virus
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Jak
dsRNA
Immune complex
FcR
TLR3
IL-10
IL-10R
dsRNA
IFN α/β R
LPS/CD14
TLR4
IFN-β
SOCS3 SOCS1?
Stat1
Sp1
PKR IRF3
ISRE
NF-κB
κB
Primary antiviral response
?
ISRE/GAS
Secondary antiviral response
• 2–5OAS • IRF1/7 • PKR • Stat1
TRENDS in Immunology
Fig. 1. Proposed model for ADE and FcgR ligation-mediated inhibition of LPS and dsRNA-stimulated antiviral responses (adapted from Refs [2,6– 9,14], figure modified from [13]). Immune-complexed virus stimulates IL-10 production following FcR ligation plus an unknown LPS- or dsRNA-derived activation signal (denoted by dotted line and a ?). IL-10 induces SOCS protein expression, which inhibits IFN-a/b receptor signalling. This prevents full activation of LPS and dsRNA-induced antiviral responses, which require the autocrine IFN-a/b and IRF positive feedback loop. Nuclear transcription is denoted by blue shading. Abbreviations: ADE, antibody-dependent enhancement; dsRNA viral double stranded RNA; GAS, interferon-a/b (IFN-a/b) activation sequence; IL-10, interleukin-10; IRF, IFN response factor; ISRE, interferon stimulated response element; kB, NF-kB response element; LPS, lipopolysaccharide; 2-5 OAS, 2-5 oligoadenylate synthase; PKR, RNA-dependent protein kinase; Sp1, transcription factor regulating IL-10 induction; SOCS, suppressor-of-cytokine-signalling.
infections. LPS is not involved in infections by RNA viruses, which normally trigger antiviral responses through binding of viral double-stranded RNA (dsRNA) to RNA-dependent protein kinase (PKR) and/or TLR3 [3,13]. However, it has emerged that the genes upregulated by LPS and dsRNA show remarkable overlap, with both appearing to be dependent on autocrine IFN-b production (Fig. 1), which produces a positive feedback loop crucial for full activation of both antiviral and antibacterial responses [13]. This contention is supported by the observation that LPS activation is compromised in macrophages from IFN-a/b receptor knockout mice [14]. If FcgR ligation can suppress both antiviral and antibacterial responses, why has ADE for bacterial infections of macrophages not been widely reported? Several bacteria specifically target macrophages but they have evolved their own specific strategies to trigger IL-10 production [9], which might (like viral IL-10) render ADE-promoted IL-10 production obsolete. Nevertheless, bacterial ADE has been reported for several bacteria in certain systems, although the mechanisms involved have yet to be fully elucidated [15]. Relevance of ADE in vivo Does this newly postulated ADE-mediated activity help in understanding ADE driven immunopathology? Certainly, IL-10 levels correlate with fatal outcomes in Ebola infections [16] and disease severity in dengue infections [17]. However, during dengue haemorrhagic fever (DHF), tumor necrosis factor-a (TNF-a) is thought to be associated with the potentially fatal plasma leakage, and IL-10 is known to inhibit this cytokine. Although these data might seem contradictory, the timing and location of IL-10 production during dengue infections could be important. One might speculate that local autocrine IL-10 is detrimental early in infection, contributing to the elevation of the peak viraemia. However, DHF mortality risk and plasma leakage occurs after the peak viraemia and after http://treimm.trends.com
defervescence, by which time systemic IL-10 has actually dropped [17], and might be present at levels insufficient to inhibit TNF-a-mediated immune pathology. The ability of IL-10 to inhibit TNF-a also appears to operate through a SOCS-independent mechanism, with recent evidence suggesting that IL-10 can suppress TNF-a transcription by the induction of Heme oxygenase through the p38 pathway [18]. Alternative mechanisms for ADE of disease The traditional view of the immunopathological consequence of ADE of macrophage and monocyte infection is that antibody (or complement) enhances virus uptake by the FcR (or complement receptor) leading to increased infection, virus yield and thus disease severity [1]. The data reviewed here suggest that FcR signalling together with viral infection might contribute to enhancing virus replication by inhibiting the innate antiviral response of the host cell through the induction of IL-10; a process that again would lead to increased virus yield and disease severity. An additional mechanism has recently been proposed, which suggests that ADE might bias the antidengue T-cell immune response towards a Th2 phenotype, with the Th2 cytokines (including IL-10) suppressing production of protective IFN-g by Th1 cells [19]. This view is supported by the observation that IgG-complexed antigen targeted to FcRs on activated macrophages deviates the immune response towards a Th2 phenotype. Interestingly, this deviation appears to be driven by macrophage IL-10 production, which is induced when the FcRs are ligated on activated macrophages [20]. More data is required before we can judge the relative contributions of the different postulated immunopathological mechanisms of ADE of disease. However, the new insights into ADE highlight several new potential players that might provide a causal link between ADE and human disease.
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References 1 Sullivan, N.J. (2001) Antibody-mediated enhancement of viral disease. In Current Topics in Microbology and Immunology, 260 Antibodies in Viral Infection (Burton, D.R., ed.), pp. 145 – 169, Springer-Verlag 2 Mahalingam, S. and Lidbury, B.A. (2002) Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kB) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc. Natl. Acad. Sci. U. S. A. 99, 13819 – 13824 3 Mahalingam, S. et al. (2002) The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses. J. Leukoc. Biol. 72, 429 – 439 4 Takai, T. (2002) Roles of Fc receptors in autoimmunity. Nat. Rev. Immunol. 2, 580– 592 5 Gerber, J.S. and Mosser, D.M. (2001) Reversing lipopolysaccharide toxicity by ligating the macrophage Fcg receptors. J. Immunol. 166, 6861 – 6868 6 Berlato, C. et al. (2002) Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J. Immunol. 168, 6404 – 6411 7 Ito, S. et al. (1999) Interleukin-10 inhibits expression of both interferon-a- and interferon-g-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93, 1456 – 1463 8 Song, M.M. and Shuai, K. (1998) The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferonmediated antiviral and antiproliferative activities. J. Biol. Chem. 273, 35056 – 35062 9 Redpath, S. et al. (2001) Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86 – 92 10 Barrionuevo, P. et al. (2001) Immune complexes (IC) down-regulate the
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basal and interferon-g-induced expression of MHC class II on human monocytes. Clin. Exp. Immunol. 125, 251– 257 Novak, N. et al. (2001) Engagement of FceRI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells. J. Immunol. 16, 797– 804 Nigou, J. et al. (2001) Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J. Immunol. 166, 7477– 7485 Doyle, S.E. et al. (2002) IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17, 251 – 263 Vadiveloo, P.K. et al. (2000) Role of type I interferons during macrophage activation by lipopolysaccharide. Cytokine 12, 1639– 1646 Haralambieva, I.H. et al. (2002) Monoclonal antibody of IgG isotype against a cross-reactive lipopolysaccharide epitope of Chlamydia and Salmonella Re chemotype enhances infectivity in L929 fibroblast cells. FEMS Immunol. Med. Microbiol. 33, 71 – 76 Baize, S. et al. (2002) Inflammatory responses in Ebola virus-infected patients. Clin. Exp. Immunol. 128, 163 – 168 Green, S. et al. (1999) Elevated plasma interleukin-10 levels in acute dengue correlate with disease severity. J. Med. Virol. 59, 329 – 334 Lee, T.S. and Chau, L.Y. (2002) Heme oxygenase-1 mediates the antiinflammatory effect of interleukin-10 in mice. Nat. Med. 8, 240– 246 Yang, K.D. et al. (2001) Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFN-g production. J. Med. Virol. 63, 150 – 157 Anderson, C.F. and Mosser, D.M. (2002) Cutting edge: biasing immune responses by directing antigen to macrophage Fcg receptors. J. Immunol. 168, 3697– 3701
1471-4906/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1471-4906(03)00065-6
| Letters
Granulomas are not just gizmos for immunologists Michael J. Doenhoff School of Biological Sciences, University of Wales Bangor, Deiniol Road, Bangor, Gwynedd LL57 2UW, UK
The January 2003 issue of Trends in Immunology carried a detailed and comprehensive insight into molecular aspects of immune granulomas, particularly those caused by schistosome eggs and mycobacteria, by Sandor et al. [1]. Unfortunately, the authors devoted little space to some comparative and basic biological data that could explain the adaptive significance of infection-induced granulomatous inflammation and render the granuloma more than a plaything for immunologists. Early in the article the authors contend that: ‘Despite the potential for damaging pathology … granuloma formation is protective for the host’. Mycobacteria are a clear example that is consistent with this intuitive assumption, in that the T-cell-dependent, inflammatory reaction they generate does indeed protect the host by prolonging life but at the expense of extensive damage to infected (lung) tissue. The analysis of schistosome granulomas within the Review of Sandor et al. deals solely with those induced by Schistosoma mansoni eggs, an understandable restriction because S. mansoni is the schistosome species most easily Corresponding author: Michael J. Doenhoff ([email protected]). http://treimm.trends.com
maintained in laboratory culture, and therefore it has been the most studied. However, the genus Schistosoma comprises nearly 20 species, two of which, Schistosoma haematobium and Schistosoma japonicum, in addition to S. mansoni, are important human pathogens. S. haematobium egg granulomas, similar to those of S. mansoni, are immune response-dependent hypersensitivity reactions [2]. Interestingly, S. mansoni eggs can be used to sensitise for enhanced granuloma formation around S. haematobium eggs but not conversely [2,3]. The inflammatory reactions against the two species of egg, therefore, probably share many of the molecular characteristics highlighted by Sandor et al. [1]. By contrast, early work on the S. japonicum egg granuloma raised doubts as to whether it was an immune hypersensitivity reaction at all, that is, one subject to anamnestic recall similarly to S. mansoni and S. haematobium granulomas. Sensitisation was not achieved by injection of whole S. japoinicum eggs or intraperitoneal injection of egg products but only by subcutaneous injection of egg antigens with Freund’s complete adjuvant [4]. The inflammatory response to S. japonicum eggs was likened to a non-immunological ‘foreign-body reaction’ [5].
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Suppression of antiviral responses by antibodydependent enhancement of macrophage infection Andreas Suhrbier and May La Linn Queensland Institute of Medical Research and the Australian Centre for International & Tropical Health & Nutrition, 300 Herston Road, Herston, Queensland 4029, Australia
Antibody-dependent enhancement (ADE) of macrophage and monocyte infection has been demonstrated in vitro for some of the most deadly RNA viruses known. Recent evidence suggests that ADE-mediated ligation of Fc receptors might suppress host-cell antiviral gene expression by promoting early interleukin-10 (IL-10) secretion, resulting in the expression of suppressor-of-cytokine-signalling (SOCS) proteins and a Th2 bias. These findings provide potential new insights into how ADE might enhance viral infections and exacerbate disease. The ability to infect productively macrophages and monocytes and demonstrate antibody-dependent enhancement (ADE) of macrophage and monocyte infection has been shown in vitro for many RNA viruses, several of which cause some of the deadliest diseases known [1] (Table 1). Curiously, although several DNA viruses can also infect these cells (e.g. cytomegalovirus, poxviruses, adenovirus), ADE has not been widely reported for these viruses. ADE is believed to involve enhanced virus uptake by Fcg receptors (FcgR) when the virus is bound by sub- or non-neutralising antibody, resulting in an increase in virus production, viraemia and pathogenesis [1]. However, a clear correlate between ADE in vitro and ADE-mediated immunopathogenesis in vivo has proven elusive. Even for dengue infections, in which the ADE-phenomena is best described, the role of ADE appears to be difficult to distinguish from other factors, such as virus virulence and the genetic predisposition of the host [1].
…a clear correlate between ADE in vitro and ADE-mediated immunopathogenesis in vivo has proven elusive. Recently, Mahalingham and Lidbury reported that ADE of macrophage infection by the alphavirus, Ross River virus (RRV) was able to inhibit lipopolysaccharide (LPS)-induced antiviral gene activation [2]. This observation suggested that, aside from enhancing viral uptake, ADE might suppress the innate antiviral response of the Corresponding author: Andreas Suhrbier ([email protected]). http://treimm.trends.com
host. The principle first-line defence of the host against RNA viruses involves rapid activation of the interferona/b (IFN-a/b) system, and many RNA viruses have developed strategies to inhibit one or more components of this system [3]. A well known strategy used by alphaviruses (and poliovirus) is rapid shutdown of host-cell translation, which prevents expression of antiviral proteins and transcription factors. Although RRV replication was required, translational shutdown did not appear to be responsible for the specific inhibition of antiviral gene activation by RRV ADE [2]. Thus, the important question is whether enhanced virus uptake mediated by ADE simply expedites deployment of some new alphaviral countermeasure against host defences, or whether Fcg receptor (FcgR) signalling by the antibody-complexed virus somehow contributes to suppression of the antiviral response of the host cell. FcgR-mediated anti-inflammatory signalling A well documented source of anti-inflammatory signals derived from FcR ligation is through the inhibitory FcgRIIb, the primary receptor for clearance of immune complexes in vivo, and the target of anti-inflammatory intravenous g-globulin treatment for autoimmune disorders [4]. However, FcgRIIb ligation-dependent inhibition through its immunoreceptor tyrosine-based inhibitory motif (ITIM) appears to be restricted to the inhibition of activation signals from other FcgRs, with no reports suggesting that FcgRIIb ITIM can inhibit LPS or IFN-stimulated pathways. Recently, Gerber and Mosser showed that FcgR ligation inhibited LPS-induced inflammatory cytokine production by macrophages, and illustrated that the inhibitory effect was as a result of early autocrine interleukin-10 (IL-10) secretion [5]. LPS usually induces late IL-10 production as part of a negative feedback cycle. However, LPS given in concert with FcgR ligation resulted in early IL-10 production and suppression of LPS-induced activation [5]. Importantly, Mahalingham and Lidbury found that alphavirus ADE also induced IL-10 expression, suggesting that a crucial consequence of ADE could be the induction of IL-10 promoted by FcgR ligation [2]. Both studies also illustrated that promotion of IL-10 production by FcgR ligation required a second signal, either from LPS [5] or virus replication [2].
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Table 1. Pathogenic viruses of humans for which ADE of macrophages and/or monocyte infection has been reported
a
Virus
Nucleic acid
Family
Genus
Dengue Japanese encephalitis Murry valley encephalitis Yellow Fever West Nile Tick borne encephalitis Ross River HIV Influenza A Respiratory syncytial Lassa Pichinde Rift valley fever Ebola Rabies Polio Coxsackie B3 Herpes Simplex 1
ssRNAa þ sense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA þsense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA 2 sense enveloped ssRNA þsense nonenveloped ssRNA þsense nonenveloped dsDNA enveloped
Flaviviridae Flaviviridae Flaviviridae Flaviviridae Flaviviridae Flaviviridae Togaviridae Retroviridae Orthomyxoviridae Paramyxoviridae Arenaviridae Arenaviridae Bunyaviridae Filoviridae Rhabdoviridae Piconaviridae Piconaviridae Herpesviridae
Flavivirus Flavivirus Flavivirus Flavivirus Flavivirus Flavivirus Alphavirus Lentivirus Influenza virus A,B Pneumovirus Arenavirus Arenavirus Phlebovirus Filovirus Lyssavirus Enterovirus Enterovirus Simplex virus
Abbreviations: ADE, antibody dependent enhancement; ds, double stranded; ss, single stranded.
…a crucial consequence of ADE could be the induction of IL-10 promoted by FcgR ligation. IL-10 is recognised as a key cytokine for the downregulation of inflammatory responses and can inhibit LPS activation of macrophages by stimulating the expression of the suppressor-of-cytokine-signalling 3 (SOCS3) [6]. SOCS3 is also responsible for IL-10-mediated repression of IFN-a-induced gene activation in monocytes [7], with SOCS3 (and SOCS1) identified as key inhibitors of IFNmediated antiviral activities [8]. SOCS1 and/or SOCS3 inhibit the Janus kinases (Jaks), and thereby suppress signal transduction by a number of cytokines and receptors, including IL-12, IFN-g and Toll-like receptor 4 (TLR4). Exploiting IL-10 A number of viruses and intracellular bacteria target macrophages and induce IL-10 and/or produce their own IL-10 homologues to dampen the host immune responses, and thereby stall their elimination from the host [9]. Similarly, ADE might facilitate early IL-10 production, enabling the viruses that infect macrophages to benefit from the anti-inflammatory and immunosuppressive environment created by autocrine IL-10 production [2]. There is no consensus regarding which antibody isotype or FcgR class (I, II or III) is most important for ADE; nearly all isotypes and receptors (including the complement receptor) active in one or more systems [1]. The relative efficiencies of the different FcRs in promoting early IL-10 production, and the potential ability of FcgRIIb ligation to inhibit this process, remain to be examined. However, the evidence so far suggests that, like ADE, there is little specificity. Ligation of FcgRs, scavenger and complement receptors, can suppress LPS-mediated macrophage and monocyte activation [5], and immune complexes are also able to inhibit IFN-g-mediated activation of monocytes [10]. Although not relevant for ADE, ligation of FceR (the http://treimm.trends.com
IgE receptor) on monocytes in the presence of IL-4 and granulocyte – macrophage-colony stimulating factor (GM-CSF) also results in IL-10 production [11], and engagement of the mannose receptor on dendritic cells also suppresses their ability to be activated by LPS [12]. These reports suggest that ligation of a number of receptors on cells of the monocyte – macrophage lineage can lead to broad suppressive activities consistent with IL-10-induced SOCS expression.
…ADE might facilitate early IL-10 production, enabling the viruses that infect macrophages to benefit from the anti-inflammatory and immunosuppressive environment created by autocrine IL-10 production. The model for ADE that emerges (Fig. 1) could explain why ADE operates in vitro for so many RNA viruses because inhibition of the IFN-a/b system is likely to promote replication of most RNA viruses. The model raises the question of whether ADE actually increases the uptake of virus or whether IL-10-mediated suppression of antiviral activity is responsible for enhanced virus production. The model might also explain why ADE has not been widely reported for cytomegaloviruses, poxviruses and adenoviruses. The former two viruses produce their own viral IL-10 homologues [9] and adenovirus produces the E1A protein, which blocks transcription of IFN-responsive genes [3]. Overlapping pathways for antiviral and antibacterial responses One might ask why IL-10-mediated suppression of bacterial LPS-activated inflammatory and antiviral responses has any physiological relevance in virus
Update
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Vol.24 No.4 April 2003
Jak
dsRNA
Immune complex
FcR
TLR3
IL-10
IL-10R
dsRNA
IFN α/β R
LPS/CD14
TLR4
IFN-β
SOCS3 SOCS1?
Stat1
Sp1
PKR IRF3
ISRE
NF-κB
κB
Primary antiviral response
?
ISRE/GAS
Secondary antiviral response
• 2–5OAS • IRF1/7 • PKR • Stat1
TRENDS in Immunology
Fig. 1. Proposed model for ADE and FcgR ligation-mediated inhibition of LPS and dsRNA-stimulated antiviral responses (adapted from Refs [2,6– 9,14], figure modified from [13]). Immune-complexed virus stimulates IL-10 production following FcR ligation plus an unknown LPS- or dsRNA-derived activation signal (denoted by dotted line and a ?). IL-10 induces SOCS protein expression, which inhibits IFN-a/b receptor signalling. This prevents full activation of LPS and dsRNA-induced antiviral responses, which require the autocrine IFN-a/b and IRF positive feedback loop. Nuclear transcription is denoted by blue shading. Abbreviations: ADE, antibody-dependent enhancement; dsRNA viral double stranded RNA; GAS, interferon-a/b (IFN-a/b) activation sequence; IL-10, interleukin-10; IRF, IFN response factor; ISRE, interferon stimulated response element; kB, NF-kB response element; LPS, lipopolysaccharide; 2-5 OAS, 2-5 oligoadenylate synthase; PKR, RNA-dependent protein kinase; Sp1, transcription factor regulating IL-10 induction; SOCS, suppressor-of-cytokine-signalling.
infections. LPS is not involved in infections by RNA viruses, which normally trigger antiviral responses through binding of viral double-stranded RNA (dsRNA) to RNA-dependent protein kinase (PKR) and/or TLR3 [3,13]. However, it has emerged that the genes upregulated by LPS and dsRNA show remarkable overlap, with both appearing to be dependent on autocrine IFN-b production (Fig. 1), which produces a positive feedback loop crucial for full activation of both antiviral and antibacterial responses [13]. This contention is supported by the observation that LPS activation is compromised in macrophages from IFN-a/b receptor knockout mice [14]. If FcgR ligation can suppress both antiviral and antibacterial responses, why has ADE for bacterial infections of macrophages not been widely reported? Several bacteria specifically target macrophages but they have evolved their own specific strategies to trigger IL-10 production [9], which might (like viral IL-10) render ADE-promoted IL-10 production obsolete. Nevertheless, bacterial ADE has been reported for several bacteria in certain systems, although the mechanisms involved have yet to be fully elucidated [15]. Relevance of ADE in vivo Does this newly postulated ADE-mediated activity help in understanding ADE driven immunopathology? Certainly, IL-10 levels correlate with fatal outcomes in Ebola infections [16] and disease severity in dengue infections [17]. However, during dengue haemorrhagic fever (DHF), tumor necrosis factor-a (TNF-a) is thought to be associated with the potentially fatal plasma leakage, and IL-10 is known to inhibit this cytokine. Although these data might seem contradictory, the timing and location of IL-10 production during dengue infections could be important. One might speculate that local autocrine IL-10 is detrimental early in infection, contributing to the elevation of the peak viraemia. However, DHF mortality risk and plasma leakage occurs after the peak viraemia and after http://treimm.trends.com
defervescence, by which time systemic IL-10 has actually dropped [17], and might be present at levels insufficient to inhibit TNF-a-mediated immune pathology. The ability of IL-10 to inhibit TNF-a also appears to operate through a SOCS-independent mechanism, with recent evidence suggesting that IL-10 can suppress TNF-a transcription by the induction of Heme oxygenase through the p38 pathway [18]. Alternative mechanisms for ADE of disease The traditional view of the immunopathological consequence of ADE of macrophage and monocyte infection is that antibody (or complement) enhances virus uptake by the FcR (or complement receptor) leading to increased infection, virus yield and thus disease severity [1]. The data reviewed here suggest that FcR signalling together with viral infection might contribute to enhancing virus replication by inhibiting the innate antiviral response of the host cell through the induction of IL-10; a process that again would lead to increased virus yield and disease severity. An additional mechanism has recently been proposed, which suggests that ADE might bias the antidengue T-cell immune response towards a Th2 phenotype, with the Th2 cytokines (including IL-10) suppressing production of protective IFN-g by Th1 cells [19]. This view is supported by the observation that IgG-complexed antigen targeted to FcRs on activated macrophages deviates the immune response towards a Th2 phenotype. Interestingly, this deviation appears to be driven by macrophage IL-10 production, which is induced when the FcRs are ligated on activated macrophages [20]. More data is required before we can judge the relative contributions of the different postulated immunopathological mechanisms of ADE of disease. However, the new insights into ADE highlight several new potential players that might provide a causal link between ADE and human disease.
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References 1 Sullivan, N.J. (2001) Antibody-mediated enhancement of viral disease. In Current Topics in Microbology and Immunology, 260 Antibodies in Viral Infection (Burton, D.R., ed.), pp. 145 – 169, Springer-Verlag 2 Mahalingam, S. and Lidbury, B.A. (2002) Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kB) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc. Natl. Acad. Sci. U. S. A. 99, 13819 – 13824 3 Mahalingam, S. et al. (2002) The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses. J. Leukoc. Biol. 72, 429 – 439 4 Takai, T. (2002) Roles of Fc receptors in autoimmunity. Nat. Rev. Immunol. 2, 580– 592 5 Gerber, J.S. and Mosser, D.M. (2001) Reversing lipopolysaccharide toxicity by ligating the macrophage Fcg receptors. J. Immunol. 166, 6861 – 6868 6 Berlato, C. et al. (2002) Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J. Immunol. 168, 6404 – 6411 7 Ito, S. et al. (1999) Interleukin-10 inhibits expression of both interferon-a- and interferon-g-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93, 1456 – 1463 8 Song, M.M. and Shuai, K. (1998) The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferonmediated antiviral and antiproliferative activities. J. Biol. Chem. 273, 35056 – 35062 9 Redpath, S. et al. (2001) Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86 – 92 10 Barrionuevo, P. et al. (2001) Immune complexes (IC) down-regulate the
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1471-4906/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1471-4906(03)00065-6
| Letters
Granulomas are not just gizmos for immunologists Michael J. Doenhoff School of Biological Sciences, University of Wales Bangor, Deiniol Road, Bangor, Gwynedd LL57 2UW, UK
The January 2003 issue of Trends in Immunology carried a detailed and comprehensive insight into molecular aspects of immune granulomas, particularly those caused by schistosome eggs and mycobacteria, by Sandor et al. [1]. Unfortunately, the authors devoted little space to some comparative and basic biological data that could explain the adaptive significance of infection-induced granulomatous inflammation and render the granuloma more than a plaything for immunologists. Early in the article the authors contend that: ‘Despite the potential for damaging pathology … granuloma formation is protective for the host’. Mycobacteria are a clear example that is consistent with this intuitive assumption, in that the T-cell-dependent, inflammatory reaction they generate does indeed protect the host by prolonging life but at the expense of extensive damage to infected (lung) tissue. The analysis of schistosome granulomas within the Review of Sandor et al. deals solely with those induced by Schistosoma mansoni eggs, an understandable restriction because S. mansoni is the schistosome species most easily Corresponding author: Michael J. Doenhoff ([email protected]). http://treimm.trends.com
maintained in laboratory culture, and therefore it has been the most studied. However, the genus Schistosoma comprises nearly 20 species, two of which, Schistosoma haematobium and Schistosoma japonicum, in addition to S. mansoni, are important human pathogens. S. haematobium egg granulomas, similar to those of S. mansoni, are immune response-dependent hypersensitivity reactions [2]. Interestingly, S. mansoni eggs can be used to sensitise for enhanced granuloma formation around S. haematobium eggs but not conversely [2,3]. The inflammatory reactions against the two species of egg, therefore, probably share many of the molecular characteristics highlighted by Sandor et al. [1]. By contrast, early work on the S. japonicum egg granuloma raised doubts as to whether it was an immune hypersensitivity reaction at all, that is, one subject to anamnestic recall similarly to S. mansoni and S. haematobium granulomas. Sensitisation was not achieved by injection of whole S. japoinicum eggs or intraperitoneal injection of egg products but only by subcutaneous injection of egg antigens with Freund’s complete adjuvant [4]. The inflammatory response to S. japonicum eggs was likened to a non-immunological ‘foreign-body reaction’ [5].