University of Groningen Molecular mechanisms of dengue virus infection … · 2016-03-09 · Chapter 2 24 25 Chapter 2 Molecular Mechanisms involved in Antibody-Dependent Enhancement

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Molecular mechanisms of dengue virus infectionFlipse, Jacobus

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Chapter 2

Molecular Mechanisms involved in Antibody-Dependent Enhancement of

Dengue Virus Infection in Humans

Jacky Flipse, Jan Wilschut, and Jolanda M. Smit

Publishedin:Traffic(2013),14(1):25–35.

AbstractDengue is the most common arthropod-borne viral infection in humans with ~50 million cases annually worldwide. In recent decades, a steady increase in the number of severe dengue cases has been seen. Severe dengue disease is most often observed in individuals that have pre-existing immunity against heterotypic dengue subtypes and in infants with low levels of maternal dengue antibodies. The generally accepted hypothesis explaining the immunopathogenesis of severe dengue is called antibody-dependent enhancement of dengue infection. Here, circulating antibodies bind to the newly infecting virus but do not neutralize infection. Rather, these antibodies increase the infected cell mass and virus production. Additionally, antiviral responses are diminished allowing massive virus particle production early in infection. The large infected cell mass and the high viral load are prelude for severe disease development. In this review, we discuss what is known about thetraffickingofdenguevirusinitshumanhostcells,andthesignallingpathwaysactivatedafter virus detection, both in the absence and presence of antibodies against the virus. This review summarizes work that aims to better understand the complex immunopathogenesis of severe dengue disease.

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Molecular Mechanisms involved in Antibody-Dependent Enhancement of Dengue Virus Infection in Humans

Dengue virus (DENV) infection is the most common arthropod-borne viral infection in humans with approximately 50 million cases annually worldwide. DENV is an enveloped (+)ssRNA virus of the family Flaviviridae, genus Flavivirus, with four serotypes (DENV1 – DENV4) sharing 70–80% a.a. sequence homology. The genus flavivirusalso includesyellowfevervirusandWestNilevirus(WNV). Currently, there is no prophylaxis available against DENV 1. DENV infection can result in diseases ranging from the relatively mild dengue fever (DF) to the severe, life-threatening dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS).

The question why some patients develop DF and others DHF or DSS is continuouslyunderinvestigationanddebate.Epidemiologicresearchhasidentifiedpre-existing humoral immunity against DENV as a predisposing factor for severe disease 2-4. Indeed, heterotypic antibodies, with sub-neutralizing properties, or waning concentrations of homotypic antibodies have been found to enhance DENV infectivity in vitro and in vivo 5-9. Therefore, depending on the infection history of an individual, two distinct infection mechanisms can be distinguished: infection in the absence and infection in the presence of DENV antibodies. In this review, we willdiscussthetraffickingofDENVandthesignaltransductionpathwaysactivatedduring infection in the absence of antibodies and during infection under conditions of antibody-dependent enhancement (ADE).

DENV infection in absence of antibodiesFollowing the bite of a DENV infected mosquito, the resident skin dendritic cells (DC),Langerhanscells,areamongst thefirstcells tobe infectedwithDENV10. Specifically,thesecellsspreadtheinfectionbytransferringthevirusfromtheskinto the lymph nodes 11, containing other DENV target cells such as resident DC 12-14, monocytes 6, 15 and macrophages 15-17. The latter two cell types may become the preferred host cells for viral replication as DC-derived virions appear to be muchlessefficientininfectingnewDCthaninsect-derivedvirions18. Additionally, hepatocytes can serve as host cells 16, 19, 20.

Cell bindingCell binding is mediated by the DENV envelope protein (E) and can occur through a widerangeofattachmentfactors,whoseaffinityforDENVbindingcanbeserotype-specific21.IdentifiedattachmentfactorsforDENVincludeheat-shockprotein9022, heat-shock protein 70 22, heparan sulphate 23, 24, CD14 25, GRP8/BiP 26, and a 37/67 kDahigh-affinitylamininreceptor27. Also, DENV has been found to bind to several C-type lectin receptors 13, including DC-SIGN 13, 21, L-SIGN 18, mannose receptor

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Chapter 2 Molecular Mechanisms involved in Antibody-Dependent Enhancement of Dengue Virus Infection in Humans

(CD206) 17 and C-type lectin domain family 5, member A (CLEC5A / MDL-1) 28, as well as avb3 integrins 29, 30. Currently, many factors are known to serve as attachmentfactorsforDENVinfection,butnoneofthemhavebeenidentifiedasan entry receptor for DENV infection of human cells 31. For example, when present, DC-SIGN is an important factor for DENV infection, however, mutating DC-SIGN internalization motifs abolished DC-SIGN internalization but not DENV cell entry 13.

Cell entryDENV entry depends on clathrin-mediated endocytosis 32-35. DENV has been shown to diffuse along the cell surface and to associate with pre-existing clathrin-coated pits prior to cell entry 33. Subsequently, the internalized virions are delivered to early endosomes (EEs) 32, 33. Depending on the virus strain, serotype and host cell type, DENV fuses either from the EE (pH ~ 6.0) or in a later stage of the endocytic pathway, after maturation of the EE into a late endosome (LE; pH 5.0 – 6.0) 32, 33.

Endosome maturation is pivotal for DENV fusion and escape, as depletion of v-ATPase,oradditionof lysosomotropicdrugs,which inhibit theacidificationofendosomes, impair DENV infection 13, 21, 32.Inadditiontoacidification,microtubuleintegrity and the transport proteins kinesin and dynein 36 are important factors in endosome maturation. Disruption of microtubules in ECV306 cells did not appear to inhibit infection 37, whereas in BHK-21 cells DENV2 was found to associate with dynein 38. Using single-particle tracking, both microtubule-dependent and -independent intracellular transport behaviour of DENV was seen in BS-C-1 cells prior to membrane fusion. Addition of nocodazole to these cells during infection resulted in a ~30% drop in viral infectivity suggesting that microtubule-dependent movement is important but not essential for the initiation of DENV infection 39.

Furthermore, Zaitseva and colleagues showed that DENV fusion depends not only on low pH, but also on the presence of anionic lipids in the target membrane 40. Inmammaliancells,specificanioniclipidsarelocalizedwithinthelateendosomalcompartments 41, 42, which may explain why DENV fuses predominantly from within late endosomal compartments.

Membrane fusion is facilitated by the E glycoprotein and is triggered by the low pH and lipid environment of endosomes 40, 43, 44. First the E homodimer rafts on the viral membrane dissociate into E monomers. The E monomers subsequently interact with the target membrane and this interaction facilitates the formation of E trimers. The energy released by these conformational changes is believed to drive the fusion process 45.

Post escape: replication, assembly and secretionOnce introduced into the cytoplasm, the positive sense RNA genome encodes for a single polyprotein, which is subsequently processed by autoproteases and cellular proteases to yield seven non-structural proteins (NS1, 2A, 2B, 3, 4A, 4B, and 5), as well as three structural proteins: C (capsid), prM (precursor membrane protein) and E 46. The non-structural proteins assemble in a sequential manner to initiate RNA replication 47. The prM and E proteins form heterodimers that are oriented into the lumen of the endoplasmic reticulum (ER).

In the infected cell, large membrane rearrangements are seen, including the formation of vesicles by ER membrane invagination 48. ER-remodelling was found to be independent of the unfolded protein response 49, correlating with the extent of viral replication 49, 50, and to require transport from the rough ER to the Golgi 51. For DENV,expressionandprocessingofNS4AissufficienttoinduceER-remodelling52. Both ER-remodelling and production of viral particles require additional lipids. For this,flavivirusesinducebothrelocalizationofcellularcholesterol49, 51, 53, 54, as well as increased lipid production on the ER 53, 55, 56. Furthermore, at a late stage during infection,flavivirusesinduceautophagy57 in order to liberate additional fatty acids for the continuation of replication 49. Indeed, replication is negatively affected by depletion of cholesterol 58 or inhibition of autophagy 49 and cholesterol synthesis 55.

An elegant study by Welsch and co-workers showed that the ER-derived vesicles contain the viral replication complex and have an open connection with the cytosol. The authors hypothesized that the pore serves as an exit for progeny viral RNA 48. Progeny RNA then associates with C proteins to form a nucleocapsid which buds into the ER and thus acquires a lipid membrane containing heterodimers of E and prM proteins 59.

Structural studies revealed that newly assembled immature particles have 60 hetero-oligomeric spikes, a single spike consisting of a trimer of prM/E heterodimers 60, 61. Assembled particles are then transported to the Golgi in an ADP-ribosylation factors 4 and 5 (Arf-4 and -5)-dependent pathway 62, which is possibly also microtubule- and dynein-mediated 38. Transit through the Golgi and the trans-Golgi apparatus is required for maturation 63 and secretion of DENV particles 62. Within the Golgi, the prM protein is cleaved by furin into a soluble pr-peptide and the M protein 63. The pr-peptide, however, remains associated with the E protein during exocytosis 64 to prevent premature fusion of the virion within the acidic compartments of the Golgi network. Lastly, DENV particles are secreted into the extracellular space.

Once in the pH-neutral extracellular space, the pr-peptide dissociates and the virion becomes mature and fully infectious 64-66. Furin cleavage is not very

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efficient; cells infected with DENV produce a high fraction of prM-containingparticles (~45%), which can be either fully immature or partially immature 67, 68. Fully immature DENV particles require furin-mediated cleavage upon cell entry to acquire infectivity 65, 67, 69. Dengue particles which are predominantly mature are likely infectious in a furin-independent manner. The minimal level of prM cleavage that is required for infection is as yet unknown. The viral life cycle, as discussed above, has been depicted in Fig. 1.

Fig. 1: Life cycle of dengue virus in the absence of antibodies.Thisfigureprovidesanoverviewof the life cycle of dengue virus during the infection of host cells in the absence of antibodies. Here the virus enters the cell by clathrin-mediated endocytosis, travels inside EEs and escapes from within the LE. The viral genome is translated by ribosomes on the ER and subsequently remodels this organelle to facilitate viral replication and assembly. Immature virus particles mature by furin-mediated cleavage of prM while passing through the Golgi network. Subsequently, dengue virus-particles are secreted into the extra-cellular space.

Antiviral responsesUpon DENV internalization in endosomes, the virus triggers innate antiviral responses 70, particularly expression of interferons (IFN). Both type I (a,b) and type II (g) IFNs have been recognized as important cytokines in protection against DENV infection 71-73.

Induction of IFN expression occurs after recognition of pathogens by pattern recognition receptors, which detect pathogens through highly conserved molecular motifs. Recognition of DENV occurs through the endosomal receptors: toll-like receptor (TLR)-3 (dsRNA) 70, TLR8 (G-rich oligonucleotides) 70, and TLR7 (ssRNA) 70, 74, as well as the cytoplasmic RNA helicases RIG-I (retinoic-acid inducible gene 1) and MDA5 (melanoma differentiation-associated gene 5) 75. The latter two recognize cytoplasmic viral RNA, i.e. after escape from endosomes, whereas the TLR3 and TLR7 are endosome-associated and will detect DENV within endosomes. Furthermore, C-type lectins, like DC-SIGN and CLEC5A, are not only important for cellbinding,butalsoinduceexpressionofpro-inflammatorycytokinesafterDENVbinding 28, 76. Interestingly, DENV also alters expression patterns of PRRs. For example, DENV replication has been found to induce upregulation of TLR3, TLR4 and TLR7 77, as well as the TLR-independent RIG-I and MDA5 in the monocytic THP-1 cell line 78. Activation of the TLR-dependent and -independent pathways hasbeenshown to induceexpressionofpro-inflammatorycytokines, IL8, IL12,IFNa, and IFNg, in THP-1 cells 79 and primary monocyte-derived macrophages 80. Upregulation of IL8 expression, mediated by nuclear factor kB (NF-kB), has also been detected in primary monocytes 81. IFN expression subsequently activates STAT1 82, and upregulates IRF1 (IFN regulatory factor 1) expression, resulting in a strong production of nitric oxide radicals (NOs) 79. The combined action of IFNs and NOs results in an antiviral state in bystander cells 83, 84 and limits replication in infected cells, respectively 85. We modelled these effects in Fig. 2A.

Clearance of infectionOnceanefficientantiviralstatehasbeenestablished,cellslikemacrophagesandnatural killer cells can clear infection 86.Additionally,DENV-specificBandTcellsare generated approximately 6 days post-infection and these will help to completely control the infection. Dengue virions will be recognized by antibodies directed against the structural DENV proteins E and prM 87-90. A recent article suggested that the majority of the antibodies generated in humans target the prM protein 90, although others have found a dominant response against E 87-89, 91, 92. Antibody-mediated neutralization of viral infectivity may occur at two levels: (i) at the level of cell binding, through inhibition of the interaction of the virus with cell-surface receptors 93, 94 and (ii) at the level of viral fusion, through binding of antibodies to e.g. the E protein fusion loop 95, 96, or through blocking of the conformational changes of the E glycoprotein that are required for membrane fusion 97-101. Several factors determine the neutralizing potency of an antibody; these include the strength of binding and the accessibility of the epitope on the virus surface 99, 102-104, the latter being strongly dependent on the maturation state of the virus 105.

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Fig. 2: Host cell factors and cell signalling pathways involved in dengue virus infection. (A) Dengue virus infection in absence of antibodies. Here, an overview is given of the signalling pathways activated by dengue virus during its viral life cycle. Dengue virus enters host cells by interacting with cellsurfacereceptors,e.g.C-typelectins,followedbyclathrin-mediatedendocytosisandtraffickingintoendosomes. Here, the virion delivers its genome into the host cytosol. The presence of dengue virus can be sensed by receptors on the cell surface, in the endosomes, or in the host cytosol. Detection of dengue virus can initiate signalling pathways culminating in expression of antiviral factors, which on theirturncanactivateanantiviralstateinbystandercells.B)ADEofdenguevirusinfection.Thisfigureprovides an overview of immuno-suppressive factors induced by dengue virus - antibody-mediated Fc receptor-ligation, as well as downregulated expression of several virus-sensors, i.e. TLR, RIG-I, and MDA5. Taken together, these effects result in a suppressed antiviral state relative to infection in absence of dengue virus-antibodies.

Infection under ADE-conditionsUpon a secondary, heterologous, DENV infection, pre-existing plasma cells are triggered to rapidly produce antibodies but these are predominantly directed against the initial DENV serotype, a process often referred to as ‘original antigenic sin’ 106-108. While most of the produced antibodies will bind to the heterologous virus serotype, they are more likely to have non-neutralizing properties against the new serotype than towards the original serotype 87, 89, 90. Surprisingly, these non-neutralizing antibodies have been found to enhance infection, a phenomenon called ‘ADE’ 5, 6, 9, 107.Enhancementisfacilitatedthroughefficientinteractionofthevirus-antibody complex with Fc receptors, which will be discussed in more detail below. Given the lack of knowledge on the steps after escape of the genome from the endosome, the current hypothesis is that all cellular changes associated with ADE are induced prior to escape out of the endosome. Thus, we will discuss only these steps.

All E antibodies tested to date have been shown to enhance standard DENV preparations when the concentration of the antibody is below the threshold required for neutralization. Interestingly though, the enhancing properties of some E antibodies appear to be dependent on the maturation status of the virus 109. The structural organization of the E protein in mature versus immature particles isverydistinctandthereforeaffectstheaccessibilityofspecificepitopesandthusthe threshold for antibody neutralization 105.Indeed,Eantibodieswereidentifiedthat preferentially enhance infectivity of immature virions 110. Other E antibodies were found to interact with immature particles but could not rescue the infectious properties of these particles whereas enhancement was seen in standard preparations 109. Antibodies directed against prM target specifically (partially)immature DENV via the pr peptide. Furthermore, prM antibodies were found to be highly cross-reactive to all DENV serotypes, and generally have poor neutralizing capacity 63, 90. In fact, recent studies showed that prM antibodies enhance the infectivity of essentially non-infectious immature DENV particles 69, 90. A few studies indicate that during secondary infection, in particular, the prM antibody repertoire isamplified90, 92.

ThecurrenthypothesisisthatDENVparticlesemployADE-specificpathwaysto enter and infect cells, leading to a higher number of infected cells (extrinsic ADE), as well as altered immune responses, and subsequently increased virus production per infected cell (intrinsic ADE). In this chapter, we will review these three phenomena separately, starting with what is known on the entry pathway of opsonized DENV particles.

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Cell bindingAs indicated above, during DENV ADE, cell binding occurs by the Fcg receptor (FcgR) 111, 112 expressed on monocytes, macrophages and DC 113. Thus, DENV targets the same host cells in the presence or in the absence of DENV antibodies. The FcgR family consists of three classes (I – III), with decreasing affinity forantibodies going from I to III 114. Yet, FcgRIIA appears to be more permissive to ADE than FcgRI 77, 111suggestingthatbindingaffinityisnottheonlydeterminantofinfectivity.

An elegant study of Boonnak and colleagues showed that immature DC (iDC) express FcgRIIa to levels similar to those found in mature DC (mDC). However, iDC do not support ADE 12, 14, 113. The authors observed an inverse relationship between DC-SIGN expression levels and DENV ADE 14. DC-SIGN expression levels decrease going from iDC to mDC to monocytes. Reduction of DC-SIGN expression reduces cell permissiveness to DENV infection in the absence of antibodies, and thus augments the relevance of virus entry through FcgR during ADE of DENV infection in mDC.

Antibody-opsonization has been found to facilitate cell binding of immature DENV particles by interaction with FcgRII 69, 90. Interestingly, under optimal conditions of ADE, a near-wildtype binding efficiency was seen for antibody-opsonized immature particles and in combination with intracellular furin cleavage, as discussed in detail below, immature DENV particles turn highly infectious 69, 90.

Cell entryFcgR not only facilitate virus-cell binding, but also cell entry, during DENV ADE, as disruption of the FcgR cytoplasmic tail or activation motifs within the tail abolishes ADE mediated by FcgRI 111 or FcgRIIa 112. Similar effects were observed when antibodies against these receptors were studied 69, 77.

As mentioned before, FcgRIIA appears to be the most permissive FcgR for DENV ADE. This property may be dependent on the ratio of expression levels of FcgRI and FcgRIIA, but may also depend on the internalization pathways followed by FcgRI- or FcgRIIA-ligands 77. For example, different pathways may delivertheopsonizedparticlesintomorebeneficialenvironmentsforthevirustoinitiate infection. FcgR-mediated phagocytosis has been found to be negatively regulated by FcgRIIB 115. A high antibody density on the viral particle ligates FcgRIIB 116, and can inhibit phagocytosis, and infection, irrespective of whether the antibodies themselves possess neutralizing properties. This also suggests that FcgR-mediated phagocytosis is an important entry mechanism involved in DENV ADE, as has been long hypothesized 5.

In the phagocytosis entry model, the presence of DENV-antibodies will enhance cell binding and entry by phagocytosis. In line with the role of phagocytosis in DENV-cell entry, there seems to be a relationship between the phagocytic activity of cells and DENV-infectivity 111, 112. Yet, two different entry mechanisms have been identifiedforWNVinthepresenceofantibodies:first,singleopsonizedparticlesseem to enter into coated pits similar to the primary infection 117, 118. Second, antibody-mediated aggregates of multiple particles appear to be phagocytized 117. Based on this closely related virus, both entry mechanisms may be important for DENV entry under ADE-conditions. Furthermore, it is not known whether FcgR-mediated entry delivers opsonized DENV into the same entry route used during infection in absence of antibodies or side-tracks opsonized DENV into a different pathway.

Immature particles are likely to be delivered to endosomes after binding and FcgR-mediated entry. It is proposed that the acidic conditions in the endocytic pathway induce conformational changes in the prM/E heterodimers similar to the maturation of virions in the secretory pathway 60, 61, 65, 119. These conformational changes facilitate cleavage of prM by host cell furin 69. It is unclear how the pr-peptideisreleased,butonecouldspeculatethatthecomplexisfirstrecycledbackto the pH-neutral cell membrane or that pr dissociates in endosomes because of the more acidic environment compared to trans-Golgi network 66. Furin-mediated cleavage and prM/E dissociation are required to enable the E protein to initiate fusion of the viral membrane with the endosomal membrane 69, 119-121. The route and traffickingdynamicsofantibody-opsonizedimmatureDENVareasyetunknown.

Modulation of the immune responseEntry of DENV via antibodies appears to remodel and suppress the innate immune response thereby favouring virus particle production in infected cells. This phenomenon has been called intrinsic ADE and can occur along both TLR-dependent and -independent pathways. However, the exact mechanisms remain to be elucidated. Below, we will address this topic, and in Fig. 2B we have modelled the current knowledge in this area.

Adaptation of the innate immune systemUsing the THP-1 cell line, Modhiran and colleagues have shown that DENV ADE targets the TLR signalling pathway by upregulating the negative TLR-expression regulators SARM (sterile-alpha and armadillo motif containing protein) and TANK (TRAF family member-associated NF-kB activator), and subsequent downregulation of TLR3, TLR4, TLR7 expression, and of TLR-signalling molecules 77,

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using an unknown pathway 122. TLRs signal through two distinct pathways, either by activating the NF-kB and subsequent IRF1 through canonical IKKs (inhibitor of k B kinase) 123, or by activating IRF3 through IKK-related kinases 124. A recent article suggested that TANK negatively regulates activity of canonical IKKs by facilitating complex formation between IKK-related kinases and canonical IKKs 125, signifying that DENV ADE shifts TLR signalling via NF-kB to signalling along a non-NF-kB pathway. Also TANK functions to limit TLR signalling along the MyD88 adaptor protein 126. Taken together, DENV ADE appears to reduce TLR expression and signalling to facilitate ongoing virus replication in the host cell.

Furthermore, Ubol et al. found that ADE enhances expression of DAK and Atg5-Atg12, which subsequently reduce expression of RIG-I and MDA5 in THP-1 cells 127. However, in monocyte-derived-macrophages, RIG-I is unaffected 128, and MDA5 might be modestly decreased under ADE conditions in both cell types 78, 128.Thus, themodificationof theTLR-independentgenesappears tobe lesspronounced than the expression of those genes that are TLR-dependent.

DENV ADE has been shown to be accompanied by reduced IFNb expression 127, 128, indicating that ADE indeed suppresses induction of an antiviral state. Rather, induction of type I IFNs appears to be dependent on high, neutralizing, concentrations of antibodies 113, which is in line with reduced phagocytosis after FcgRIIB ligation 116. In contrast, a recent report of Kou and colleagues measured type I interferon by DENV-infected PBMCs, using an elegant VSV infection-inhibition assay.Atfirstglance,ADEappeared to result inhigherand longersecretionoftype I IFNs, visualized by complete inhibition of VSV infection 129. However, as VSV infection is very sensitive to type I IFNs 130, the enhanced infection under ADE conditions relative to DENV infection in absence of antibodies may actually have resulted in a higher number of DENV-infected, IFNa/b-producing cells at any time point 131, with an associated higher inhibition of VSV. Thus type I IFN production during DENV ADE still may be lower on a per-cell basis.

Type I IFNs induce an antiviral state by activating the JAK/STAT pathway, which subsequently activates STAT-1/2, IRF-1/-3 and production of NOs 132. NOs are potent inhibitors of DENV replication 85 and viral protease activity 133. In line with the work by Ubol et al. 127, Chareonsirisuthigul et al. 79 found that ADE results in reduced levels of NOs in THP-1 cells, due to blocked activation of STAT-1 and expression of IRF-1. As described above, the affected IRF-1 levels may also be due to upregulation of TANK expression and an associated shift in TLR-signalling along canonical IKKs to IKK-related kinases.

Inhibition of the JAK/STAT pathway was found to be mediated through upregulation of SOCS3 (suppressor of cytokine signalling 3) 134 in both monocyte-

derived-macrophages 128 and THP-1 cells 127. SOCS3 upregulation in THP-1 was mediated through increased levels of IL10 79, 127, an immunosuppressive cytokine, the expression of which would be induced by FcgR ligation, as previously observed for opsonized amastigotes 135 and Ross River virus 136. By contrast, in primary monocyte-derived-macrophages 128, IL6 upregulation is responsible for SOCS3 upregulation,andthis is in linewith thefindingofBoonnakandcolleagues thatIL6 expression is maximal at peak ADE in primary monocytes and monocyte-derived-macrophages 113. Enhanced IL6 levels were also found in THP-1 cells under ADE conditions, although less pronounced than for IL10 and its role was not further investigated 79. Therefore, it remains to be investigated whether SOCS3 upregulation is induced by IL10 and IL6 independently, or mainly by IL6.

Intrinsic ADEAs described above, DENV infection in the presence of antibodies may skew the innate antiviral response towards a virus-tolerant state within the cell, so-called intrinsic ADE 9. Suppression of the innate immune system during DENV ADE likely facilitates longer survival of infected cells and thus increased total virus output 78,

79, 113, 129. Kou et al. noted that, under ADE conditions, the number of infected human

PBMCs is doubled, but that the viral output increased 10-fold 129. Similar observations have been made by Boonnak et al. in monocytes (4-fold, and 1500-fold, respectively), mDC (2.5-fold, and 3000-fold, respectively), as well as monocyte-derived-macrophages (7-fold, and 2000-fold, respectively) 113. These results suggest that ADE activates an intrinsic pathway resulting in enhanced virus production per infected cell. It should be noted that the increased number of infected cells in DENV ADE infected samples had not been compensated. When compensationwasappliedtoyieldsimilarnumbersofinfectedcells,nosignificantlyincreased viral output was observed between normal infection and infection under ADE conditions using wildtype DENV in mDC 14 and immature virus in the K562 cell line 69 suggesting that enhanced cellular virus production may be more related to extrinsic ADE rather than alterations in intracellular pathways (intrinsic ADE).

Conclusions and challengesThe development of severe dengue disease is a multifactorial process in which the presence of pre-existing heterologous antibodies plays an important role. Severe disease is often preceded by high circulating virus titres and already in the early 1970s it was hypothesized that non-neutralizing heterologous antibodies stimulate

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the infectious properties of the virus thereby causing an increased viral load and enhanced disease. Recent studies in this area, as highlighted in this review, revealed that ADE of infection is driven by two main elements: (i) an increased number of infected cells, due to increased antibody-mediated cell binding and entry of both mature and (partially) immature DENV particles, also known as extrinsic ADE; (ii) enhanced virus production per infected cell due to suppression of the innate antiviral response. The latter process is called intrinsic ADE and appears to mainly stem from suppressed TLR-signalling, although more research is required to fully understand this phenomenon.

A future challenge for ADE research is to characterize the cell entry pathway used by antibody-opsonized DENV. It will be of importance to determine whether antibody-opsonized DENV is internalized through a different cell entry pathway, compared to non-opsonized virus, thereby providing a more favourable environment for cytosolic escape of the DENV genome, or assisting the virus to avoid detection by PRRs at the site of genome escape 77.

The current literature suggests that the reduced antiviral response observed under ADE conditions is triggered during the early stages (binding, entry) of the viral life cycle. Yet, many effects, e.g. cytokine expression levels, are measured at later time points, up to 48hr post-infection, near the end of the second round of infection. One could speculate that the effects at later time points are associated with transcription and translation of the DENV genome 137-139 rather thanspecificstepsduringviralentry.Indeed,UV-inactivatedDENVfailstoaffectcytokine production, even under ADE conditions 14, 77, 113. To further understand the phenomenon of intrinsic ADE it would be interesting to investigate the differences ingeneexpressionpatternswithinthefirsthourspost-infectionratherthan18–24hours or even days post-infection.

Continued research on this topic is required to fill important gaps in ourknowledge in the immunopathogenesis of severe dengue disease and may guide thedevelopmentofsafeandefficaciousantiviraldrugsandvaccines.

AcknowledgementsWe thank the reviewers, I.A. Rodenhuis-Zybert, and M.J. Schuijs for reading the manuscript. JF and JMS acknowledge support from the Dutch Organization for Scientificresearch(NWO-VIDI).

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