Dengue Virus Pathogenesis: an Integrated View

Byron E. E. Martina,* Penelope Koraka, and Albert D. M. E. Osterhaus
Erasmus MC, Department of Virology, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands INTRODUCTION................................................................................................................. .....................................564 THE PATHOGENESIS OF DENV INFECTIONS: CURRENT HYPOTHESES...............................................565 DENV Tropism................................................................................................................. ......................................565 Cells of the immune system ..............................................................................................................................565 Organ pathology.............................................................................................................. ...................................565 EC .................................................................................................................................. ......................................566 Virus Virulence.......................................................................................................................................................566 Activation of the Complement System.......................................................................................... .......................567 Transient Autoimmunity.............................................................................................................................. .........567 Host Genetic Factors.............................................................................................................................................567 Antibody-Dependent Enhancement ....................................................................................................... ...............568 Cross-Reactive T-Cell Response ...........................................................................................................................569 Soluble Factors.............................................................................................................. .........................................569 THE INTERGRATED VIEW......................................................................................................... ...........................571 DISCUSSION.............................................................................................................................................................573 ACKNOWLEDGMENTS ............................................................................................................. .............................574 REFERENCES ............................................................................................................................. ..............................574 INTRODUCTION Dengue virus (DENV) belongs to the family Flaviviridae, genus Flavivirus, and is transmitted to humans by Aedes mosquitoes, mainly Aedes aegypti. Based on neutralization assay data, four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) can be distinguished. DENV infection is a major cause of disease in tropical and subtropical areas, with an estimated 50 million infections occurring each year and more than 2.5 billion people being at risk of infection (75). Infection with any of the DENV serotypes may be asymptomatic in the majority of cases or may result in a wide spectrum of clinical symptoms (87), ranging from a mild flu-like syndrome (known as dengue fever [DF]) to the most severe forms of the disease, which are characterized by coagulopathy, increased vascular fragility, and permeability (dengue hemorrhagic fever [DHF]). The latter may progress to hypovolemic shock (dengue shock syndrome [DSS]). In Asia the risk of developing severe disease is greater in DENV-infected children (_15 years) than in adults (30, 80, 109, 172). In contrast, in the Americas mainly the adult population is affected, resulting in mild disease (84, 186, 188), although an increasing trend of cases progressing toward DHF/DSS has also been observed in adults there (75, 79, 87, 126, 186). DF is manifested as an incapacitating disease in older children, adolescents, and adults. It is characterized by the rapid onset of fever in combination with severe headache, retro-orbital pain, myalgia, arthralgia, gastrointestinal discomfort, and usually rash. Minor hemorrhagic manifestations may occur in the form of petechiae, epistaxis, and gingival bleeding. Leukopenia is a common finding, whereas thrombocytopenia may occasionally be observed in DF, especially in those with hemorrhagic signs (76, 109). The World Health Organization (WHO) classifies DHF in four grades (I to IV). DHF grades I and II represent relatively mild cases without shock, whereas grade III and IV cases are more severe and accompanied by shock. DHF is characterized by all the symptoms of DF, in combination with hemorrhagic manifestations (positive tourniquet test or spontaneous bleeding), thrombocytopenia, and evidence of increased vascular permeability (increased hemoconcentration or fluid effusion in chest or abdominal cavities). The life-threatening DSS stage occurs at the time of or shortly after defervescence, which is characterized by a rapid, weak pulse (_20 mm Hg) or hypotension with cold, clammy skin in the early stage of shock (grade III). If patients do not receive prompt and appropriate treatment, a stage of profound shock may set in, in which pulse and blood pressure become undetectable (grade IV), resulting in death within 12 to 36 h after

onset of shock (262a). It is important to realize that the WHO case definition was originally proposed as a tool for clinical diagnosis using the results of repeated clinical tests. The WHO classification system poses a problem for everyday clinical practice, because it may be not sufficiently accurate in correctly classifying disease severity and may lack good agreement with clinical practice (213). Consequently, the WHO classification system is currently being reconsidered, and a new classification system is to be expected soon. The stage of prolonged shock may trigger or accelerate the development of disseminated intravascular coagulation (DIC) (228). Data that support or refute the occurrence of DIC in severe dengue are inconclusive, so better studies using prospective cohorts are needed to show the frequency of DIC in DHF/DSS patients and its association with clinical outcome (30, 152, 262). Massive loss of blood is rare in DHF and DSS and if present it is largely restricted to the gastrointestinal tract. This is usually due to prolonged shock resulting in blood being shunted away from
* Corresponding author. Mailing address: Erasmus Medical Center, Institute of Virology, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Phone: 3110 704 4279. Fax: 3110 704 4760. E-mail: b.martina @erasmusmc.nl. 564

the gastrointestinal tract, leading to anoxia, cell death, and gastrointestinal bleeding. In contrast, the mild forms of hemorrhages seen early in infection, such as petechiae, result from different mechanisms related to virus infection in combination with the release of vasculogenic cytokines. Understanding the mechanism underlying the development of shock is crucial for the development of novel strategies to improve patient management. It is worth noting that patients classified as having DHF and DSS have no generalized edema; rather, a selective plasma leakage tends to occur in the pleural and abdominal cavities (12, 230, 246, 252, 256), which is detectable by means of radiology or sonography. Ultrasonographic examinations have revealed that plasma leakage occurs before defervescence or changes in hemoconcentration become apparent (12, 230, 252). Attempts to explain the pathogenesis of dengue in all its complexity must consider all the clinical, immunological, pathological, and epidemiological features of DENV infection. The aim of this review is to outline the current views of DHF/ DSS pathogenesis and to identify the gaps in our knowledge that represent critical challenges for the future. THE PATHOGENESIS OF DENV INFECTIONS: CURRENT HYPOTHESES DENV Tropism Cell and tissue tropism of DENV may have a major impact on the outcome of DENV infections. The absence of an appropriate animal disease model largely hampers our understanding of the role played by DENV tropism. In vitro data and autopsy studies suggest that three organ systems play an important role in the pathogenesis of DHF/DSS: the immune system, the liver, and endothelial cell (EC) linings of blood vessels. The tropism of DENV for cells of the respective systems, the corresponding pathological effects of DENV infection of these systems, and the relevance of these events for the overall pathogenesis of DENV infection will be described. Cells of the immune system. During the feeding of mosquitoes on humans, DENV is presumably injected into the bloodstream, with spillover in the epidermis and dermis, resulting in infection of immature Langerhans cells (epidermal dendritic cells [DC]) (136, 263), and keratinocytes (136). Infected cells then migrate from site of infection to lymph nodes, where monocytes and macrophages are recruited, which become targets of infection. Consequently, infection is amplified and virus is disseminated through the lymphatic system. As a result of this primary viremia, several cells of the mononuclear lineage,

173. In general. 59). liver (13. DENV has been recovered from the spleen. in order of frequency. while abortively infected or bystander DC are stimulated to produce the bulk of mediators that are involved in inflammatory (22. spleen (13. The interpretation of the pathological findings in fatal cases of DHF/DSS in relation to viral tropism described in the literature is complicated by a skewed age distribution. 101. 101. bone marrow (13. 47. 137. DENV cell tropism can be inferred from studies that had used in situ hybridization. 101. as well as the way in which the inflammatory response affects the hemostatic system (35. lung (13. 101. Bone marrow stromal cells have also been shown to be susceptible to infection with DENV (124. and whether those cases are representative in reflecting the viral tropism in the acute phase of infection is unclear. 145) and hemostatic (48. 96. 91. autopsy is not conducted on the majority of fatal cases. 164. and consequently the levels of viremia. 104. 14. Organ pathology. 164. with high concentrations of virus isolated from the skin and gastrointestinal tract whereas low concentrations of virus were recovered from the spleen. 101. 101. or a combination of PCR and virus isolation techniques. chemokines. and bone marrow of infected AG129 mice (124).including blood-derived monocytes (59). thymus. 96. Similar organ tropism has been observed in the primate model. 91. lymph nodes. lymph node (13. In this regard. 202). immunohistochemistry. mostly children or young adolescents (4 to 18 years old) who died within 36 h of developing shock. and brain (164). liver. 101). 133. the presence of DENV in several organs was not associated with gross or microscopic evidence of severe organ pathology (17). 208). and usually families opt for rapid burial or cremation. The presence of infectious virus in these samples was not always investigated. Histopathological research is difficult to perform because fatal cases of DHF/DSS are rare and occur mainly in remote parts of the world where appropriate laboratory technology is largely lacking and thus fresh or frozen patient materials are rare. and the range of different techniques used to confirm the presence of virus in affected tissues. 173. 173). 78. Leukocytes also have been shown to be infected with DENV in experimentally infected nonhumans primates (156). 120. 92. The failure to isolate virus from most organ samples may indicate that those tissues contained primarily degraded virus or virus complexed with antibodies that prevent infection of cells in vitro. DENV has also been shown to have tropism for circulating mononuclear cells in blood and for cells residing in the spleen. revealed. peripheral lymph nodes. autopsies have been performed on only a small number of these patients. high concentrations of DENV-specific immunoglobulin G (IgG) will complex newly produced virus that adheres to and is taken up by mononuclear cells. It should be noted that during secondary infections with heterologous DENV. 182). due to cultural and religious practices. 208). myeloid DC (20. thymus (106). different times of sample collection. factors that influence the amount of target cells infected. 54d. 117) are infected. and central nervous system in alpha/beta . 199. In addition. 208). which is in agreement with the pathogenesis of DHF/DSS. 104. 199. 78. 54d. kidney (14. may determine the ratio of different proinflammatory and anti-inflammatory cytokines. 164. 14. 69. and other mediators. 236) responses of the host. the presence of DENV in cells in the skin (104). 137. 171. Although thousands of patients with confirmed dengue have been recognized in Southeast Asia and the Americas in the past 60 years. Following infection. 60. and several peripheral lymph nodes (157). 133). and splenic and liver macrophages (18. 53. 14. mononuclear cells predominantly die by apoptosis (61. 173). A review of the literature describing findings on autopsy samples from a total of 160 fatal cases. 97. but in general virus could be isolated only from liver and peripheral blood mononuclear cells. 199. 123. 78.

78. and infection results in functional rather than morphological damage. It has been proposed that the severe hepatic damage seen. which were characterized by moderate midzonal hepatocyte necrosis. DENV infection patterns in microvascular cells in vitro suggest that EC from different tissues have different activation patterns (184). for instance. but the role of hepatic damage in coagulopathy and disease severity remains to be established. The tropism of DENV for EC in vivo remains controversial. it has been proposed that the coagulation responses upon severe systemic inflammation by EC in different parts of the vascular-bed system are not the same (200. Therefore. It is interesting to note that a generally used argument in the literature is that when shock sets in. The integrity of the EC bed is physiologically regulated by many factors. 124. with some reports suggesting an association between elevated liver enzyme levels and spontaneous bleeding tendencies (54e. in yellow fever. which could account for the decreased synthesis of coagulation factors and development of coagulopathy (43. Most autopsy data did not specifically compare the presence of viral antigens or nucleic acid in blood and autopsy samples. although DENV antigen was not detected in EC but was detected in cells surrounding the microvasculature (21. 212). 19. it is conceivable that EC from the pulmonary and abdominal territories react in a specific way to either infection with or . One notable difference between humans and the mouse model is the tropism of DENV for neuronal cells. and late Ebola virus infections results in decreased liver function. 190. 254). 191). indicating that much of the observed apoptosis and necrosis was virally induced. microvesicular steatosis. Although increased peripheral microvascular permeability has been shown to occur in both DHF and DSS patients (16). Although DENV was found in a significant proportion of human hepatocytes and Kupffer cells. In agreement with these findings it was shown in the rhesus macaque model that DENV could be recovered from some autopsy samples but not from blood. there is evidence for the presence of DENV antigen in the pulmonary vascular endothelium (101). while viremia is no longer detectable (199). EC do not carry Fc receptors and thus will not take up immune-complexed virus. In contrast. 95). the presence of viral RNA in these cells would more likely be explained by a mechanism of pinocytosis (101). 261). elevated liver enzymes suggest that the liver is affected. It is not clear whether EC of different vascular-bed systems have different susceptibilities to DENV infection.interferon (IFN-_/_)-deficient mice (13. 201). Early studies of skin biopsy specimens indicated that the microvasculature located in the dermal papillae is the main site affected. little inflammation was seen within the liver. virus is no longer detectable in blood and therefore the host response should play a key VOL. Cases of dengueassociated hepatitis have been described. 267). a picture similar to what is observed in the early phase of yellow fever or Rift Valley fever (57. EC. however. 203). 181. The liver is commonly involved in DENV infections in humans and mouse models (181. that the mere presence of viral RNA or antigen in EC is no proof for viral replication. 124. It is important to realize. 269). Rift Valley fever. In vitro studies have shown that all DENV serotypes can actively replicate in EC (7. 22. In this regard. and councilman bodies (63. Although severe hepatic damage is not common in DENV infections. 166). EC play an important role in the coagulation response upon severe systemic inflammation. The higher prevalence of apoptosis over necrosis could explain the limited inflammation seen in the liver. 2009 DENGUE VIRUS PATHOGENESIS 565 role in pathogenesis (134. but the limited evidence suggests that DENV replication may occur in some organs. Similarly. In contrast to mononuclear cells.

It has also been shown that different geographical DENV strains or different serotypes may vary in their ability to infect different cell types or cause severe disease (56. 119). Analysis of DENV genomes has shown that DENV indeed evolves during an epidemic (42. 566 MARTINA ET AL. 131). the first outbreak of DHF in the Americas occurred in 1981. however. 29. age has been shown to influence the outcome of disease following a secondary infection with heterologous DENV (80). 39. Australia (234). the observation that DHF/DSS is seen primarily in a relative small percentage of secondary DENV infections and to a much lesser extent in primary infections even with allegedly virulent strains suggests that host factors must be crucial determinants of severe disease development. Remarkably. resulting in the selective vascular leakage syndrome characteristic of DHF/ DSS. 39). which coincided with the introduction of the possibly more virulent DENV-2 Southeast Asian genotype. the risk of severe disease is greater in children than in adults. MICROBIOL. 115. 251). where the adult population is mainly affected and infection results in milder disease. the higher the risk of developing severe disease. However. DENV serotypes can be further classified into different genotypes on the basis of nucleotide variations. During the 1981 DENV-2 epidemic in Cuba. 198). more data are needed to establish an association between intraepidemic virus evolution and increased disease severity. In this regard. It has been hypothesized that recognition of NS1 by anti-NS1 antibodies could then contribute to the selective pulmonary vascular leakage. it is worth mentioning that the major nonstructural protein 1 (NS1) of DENV has been shown to bind preferentially to EC of lung and liver tissues (9). Furthermore. providing a possible explanation for the profound plasma leakage seen in pleural and peritoneal cavities. 168). However. evaluated independently of the host or only in vitro or in often inbred animals.the response to DENV infection (28. it was noted that severity of disease manifestations and case-fatality rates were increased toward the end of the epidemic (118. This difference in disease severity caused by Asian and American genotypes correlated with structural differences in the two strains of DENV (51. Epidemiological observations in the Americas and in Singapore suggested that the sequence of infection with particular serotypes and the time interval between primary infection and secondary infection may play an important role in the development of DHF. 178). an increasing body of evidence . CLIN. 248). Several studies suggest that vascular damage or dysfunction is central in the pathogenesis of DHF/DSS (26. It has also been proposed that intraepidemic evolution of the circulating DENV might be responsible for increased severity of disease. REV. while the less virulent indigenous DENV-2 genotype was already circulating in the region (118. It is important to realize that virulence has traditionally been considered a microbial property. 195–197). certain DENV strains are responsible for more severe disease. and again in Cuba during the 1997 epidemic (81). these studies indicated that the longer the interval between primary and secondary infections. In addition. suggesting that the circulating DENV-2 might have become more virulent through passage in hosts during the epidemic. In Asia. It is interesting to note that selective apoptosis of the microvascular EC in pulmonary and intestinal tissues has been detected in fatal cases of DHF/DSS (137). A similar situation was observed in the 1992 DENV epidemic in Townsville. 131. in contrast to the Americas. 83. Virus Virulence According to the virus virulence hypothesis. 206. Epidemics with high incidences of DHF have been linked to primary infection with DENV-1 followed by infection with DENV-2 or DENV-3 (79. Viral genetic differences have been associated with differences in virulence (51.

they require the unlikely event of two IgG molecules binding close to the antigen in order to promote C1q binding (90). EC. The presence of serum antibodies specific to NS1 also has been shown to correlate with disease severity (134. It is important to understand what determines the threshold of activation needed and how activation participates in development of DHF/DSS. Binding of heterotypic antibodies to NS1 expressed on infected cells may result in complement activation (8. Crossreaction of anti-NS1 with cells of the liver. 174. It has been proposed that NS1 is an important trigger for complement activation (122). followed by an accelerated consumption and a marked reduction of the complement components in patients with DSS (50. 177. 159). These innate immune mechanisms provide the host with the time needed to maximally induce the more slowly developing adaptive immunity. 214). has the capacity to self-associate into multivalent complexes. Therefore. Several groups have shown that both IgG1 and IgG3 were the predominant subclasses involved in the specific antibody response in human DENV infections (116. it was hypothesized that complement activation plays an important role in the pathogenesis of dengue. on the other hand. Anti-NS1 antibodies cross-reactive with EC could trigger these . 163. 242). 237) could be at the basis of this observation. which may be implicated in intravascular coagulation. Both IgG subclasses can fix and activate the complement system effectively. Comparison of global gene expression profiles in peripheral blood mononuclear cells of DF and DHF/DSS patients also suggests the involvement of the complement system in disease severity (249). Although IgG1. 140. Alternatively. In addition.incriminates the host immune response in the pathogenesis of many microbial infections (31). 218). However. and IgG4 are able to activate the classical complement pathway. IgG3. but it is not clear if production of these antibodies is associated with secondary DENV infections. The presence of sialic acid in the glycans of IgG subclasses could also affect their complement-fixing properties (100) and possibly their infection-enhancing activity (65. the C5b-C9 complex could independently trigger other local and systemic effects (158). both host and viral factors should be considered. Activation of the Complement System The complement system is one of the main humoral components of the innate immunity and interacts closely with the hemostatic system to provide the first line of defense against pathogens. 64. Transient Autoimmunity Antibodies produced during a DENV infection have been shown to cross-react with some self-antigens. IgG2. and platelets (33. It is important to realize that coagulation enzymes can also activate the complement system. 94. illustrating the extensive interaction that exists between the complement and the coagulation system. when plasma leakage may become apparent. high levels of the activation products C3a and C5a are measured in the plasma. Therefore. 142). it is believed that NS1 released from infected cells can directly activate complement factors present in the fluid phase (122). antibodies recognizing a linear epitope in the E protein have been shown to bind human plasminogen and inhibit plasmin activity (49. thereby increasing functional affinity and the likelihood of C1q binding. Production of the C5b-C9 complex could then trigger cellular reactions and stimulate the production of inflammatory cytokines that are associated with development of DHF/DSS (8). With regard to DENV. whereas IgG2 and IgG4 are less effective in this respect (90). For instance. many aspects of complement activation and its role in DENV pathogenesis remain to be investigated. investigators noticed that around the time of defervescence. in studying DENV virulence. 266).

Although. G6PD deficiency causes abnormal cellular redox.cells to express nitric oxide (NO) and undergo apoptosis (141). Anti-NS1 antibodies have also been shown to enhance expression of interleukin-6 (IL-6). predisposing to a more severe form of disease. 204). Although NO has been shown to inhibit DENV replication (239). superoxide. antiNS1 antibodies were also shown to cross-react with human and mouse platelets and were able to cause transient thrombocytopenia and hemorrhage in mice (142. it is important to understand why the autoimmune phenomenon observed in some DENV-infected patients does not persist. Clearly. Certain host factors. resulting in a common immunodeficiency syndrome present in up to 10% of the U. Several epidemiological studies indicated that genetic factors constitute important components in disease susceptibility. Mutation in the promoter region of MBL results in low serum levels of MBL.S. Several human HLA class I and II alleles are associated with development of DHF (Table 1). 22. Fc_ receptor. CTLA-4. Therefore. Polymorphism in the tumor necrosis factor alpha (TNF-_). Oxidative stress is known to affect viral proliferation and virulence by increasing viral receptors on target cells or increasing production of viral particles (264). it is possible that G6PD deficiency provides a more suitable milieu for viral replication. indicating that such cross-reactive antiplatelet antibodies are pathogenic. and intracellular adhesion molecule 1 (ICAM-1) (138). 54c). Polymorphism in transporters associated with antigen presentation and human platelet antigen has also been associated with increased risk for developing DHF (224). the autoimmune hypothesis has remained controversial. Although it is likely that the cross-reactive antibodies to self-antigens are of the short-lived IgM isotype (139. Since the kinetics of anti-NS1 antibodies is difficult to reconcile with the short duration of the sudden hyperpermeabilty event that leads to shock. This observation may have implications for vaccine development. 2009 DENGUE VIRUS PATHOGENESIS 567 tribute to increased replication of DENV in monocytes. Deficiency in G6PD. is the most common enzyme deficiency worldwide. its overproduction could also lead to cell damage (141. MBL is a member of the collectin family and is assumed to play an important role in pattern recognition and innate immune defense. more efforts should be deployed in identifying the putative self-antigens that are recognized by anti-DENV antibodies and in understanding their role. It is worth reiterating that morphological damage is not a common observation in lethal cases of DHF/DSS. may also conVOL. especially for live-attenuated vaccines. Further studies are needed to see if crossreactivity of anti-NS1 with EC could lead to the increased permeability that is characteristic of DSS. 215). Polymorphism in the mannose-binding lectin 2 (MBL2) gene was shown to be associated with thrombocytopenia and an increased risk for developing DHF. thereby affecting production of nitric oxide. a ubiquitous X-linked enzyme. In addition. with high prevalence seen in the African population (175). and transforming growth factor _ (TGF-_) genes has been associated with development of DHF/DSS. It remains to be determined . vaccination strategies should not result in memory IgG responses to such antigens. 237). such as glucose6-phosphate dehydrogenase (G6PD) deficiency. in dengue pathogenesis. each with mild to moderate effects. The risk to develop DHF and DSS following infection with DENV is likely to be determined by a combination of multiple common genetic traits. vitamin D receptor. IL-8. and hydrogen peroxide. if any. it is worth noting that a low incidence of severe disease was reported in populations of African origin in studies conducted in Cuba and Haiti (54b. Host Genetic Factors Differences in disease severity can be seen at both the individual and population levels. population (243).

as has been identified for a number of common pathogens. Antibody-Dependent Enhancement In most acute virus infection models. These results must be interpreted . 82. 259). 235. In general. The other peak was observed in young children who had experienced an earlier. subneutralizing levels. Despite several clinical studies. ADE could result in infection of a higher number of target cells. 151). infection and were later infected with a different DENV serotype. a phenomenon that is not restricted to viral pathogens only (150). evidence for the role of ADE in human disease. the presence of viral RNA became undetectable (132). the presence of antibodies.whether single gene defects that confer profound susceptibility to DENV infection exist. and eventually protection. a phenomenon that was claimed to be caused by antibodies and termed antibody-dependent enhancement (ADE) of disease (85). Unfortunately. Furthermore. In some cases. These observations led to the conclusion that subsequent infection of preimmune individuals with a different DENV serotype could exacerbate rather than mitigate disease. usually mild or subclinical. As stated above. and NO but enhanced expression of the anti-inflammatory cytokines IL-6 and IL-10 (36). 245. 221. 238. The key observation there was that severe disease occurred in infants for whom maternal antibodies had declined to low. such as pneumococci and mycobacteria (185). However. not all cases of severe disease are associated with ADE or preceded by infection with a heterologous serotype or by high viral loads. a high viral load and the presence of virus on the day of defervescence are important risk factors for the development of severe disease. it was shown that virus replication was necessary in order to promote IL-10 expression. elimination. such as in DENV infections. 189. 111. 255). It was also shown that DENV infection of THP-1 cells via FcR suppressed the transcription and production of IL-12. 207. TNF-_. 240. IFN-_. For instance. a study with Ross River virus showed that viral entry via the Fc_R pathway could suppress antiviral genes and enhance IL-10 production in murine macrophages. Although some studies have shown a correlation between enhancing activity of serum. a possible detrimental role of virus-specific antibodies has been described for several viruses as measured by in vitro enhancement of infection of cells (72. however. 112). 245). and an increased risk for DHF/DSS (38). when DHF/DSS is seen. 251. Halstead and colleagues observed that the incidence of DHF and DSS peaked in two populations of young children. 199). high levels of viremia. individuals who develop DHF or DSS but are otherwise healthy may serve as a pool to identify polymorphism and single-gene defects predisposing to the development of the most severe forms of DENV infection. Several subsequent epidemiological studies provided further circumstantial evidence for the role of preimmunity in the pathogenesis of DHF (25. the Fc receptor that was involved in ADE was not identified. 258. and epidemiological studies have shown an increased risk of developing DHF/DSS after a secondary DENV infection (74. 98. indicating that ADE of DENV infection also resulted in a milieu that promoted viral replication. while entry via the normal cellular receptor did not change the antiviral environment (135. 93. 73. correlates with control. 80. which could lead to the high viral load observed in many studies (132. In this respect. both neutralizing and nonneutralizing. This in vitro phenomenon was also described for DENV infection (86). An alternative or complementary hypothesis is that Fc_Rmediated entry suppresses the antiviral immune response. One peak occurred in infants (at the age of 6 to 9 months) who were infected with a DENV serotype different from that which had infected their mothers. remains circumstantial. it is not completely clear whether the absence of viremia always correlates with clearance of virus from infected tissues (155.

..... In this regard....... and it is assumed that cross-reactive T cells of low avidity for heterologous virus are not protective (110).................. since the effect of ADE of infection on gene expression may be cell dependent (20)......................... ence of antibodies resulted in development of chronic infection.... increased levels of IL-10 have been associated with visceral and cutaneous leishmaniases..... It is worth noting that a consistent finding in all examples of T-cell-mediated pathology during acute or persistent viral infections is morphological tissue damage as a result of cytolysis or inflammation induced by the high numbers of effector T cells...... 180.........143 Fc_RIIa polymorphism........ and IL-10 has been flagged as having an important role in the regulation of the immune response to this parasite. but they may play a role in clearing infection as well as in immunopathogenesis (3............... which is associated with both quantitative and qualitative defects in the antigen-presenting cell (APC) population (148................................................ 114).............45 Transporters associated with antigen presentation and human platelet antigen............ DR*4.45 TNF-_308A polymorphism ......... One study conducted in Thailand reported no differences in the incidence of DHF in children who had received a live-attenuated DENV vaccine and unvaccinated controls at 6 to 8 years after vaccination (34)................... 225 DC-SIGN polymorphism ... 270 HLA class II alleles DQ*1. 232....... DR*1.......66 CTLA-4.. The role of CD8_ T cells during DENV infection is not entirely clear. Yet............................ however................... A*24..... The efficiency of activated T cells in clearing virus-infected cells is dependent on the avidity of the T-cell receptor (TCR) for the HLA-peptide complex (222). they can also cause substantial immunopathology (210)................35 MBL2 ..............144........125............... however..... B*46........... 244)......... 187 568 MARTINA ET AL........... CLIN.............. Cross-Reactive T-Cell Response Although memory T cells cross-reactive with a heterologous virus can provide partial protective immunity... Most clinical trials with candidate DENV vaccines were conducted in areas where the disease is not endemic and the chance of acquiring a natural infection is limited...... This effect of Fc_R-mediated entry on the antiviral state is not unique to viral pathogens...................... Experimental infection of monkeys with DENV-1 or DENV-4 followed by a secondary infection with DENV-3 a year later did not result in increased viremia or disease (113)................ there are only a handful of virus-animal models where heterologous immunity ....................... A*0207. since the interval between primary and secondary infection may have been too short......... MICROBIOL....... thereby linking ADE to Th2 immune responses. REV. Summary of non-HLA and HLA-associated genetic factors involved in the development of DHF/DSS Genetic factor Reference(s) Vitamin D receptor polymorphism ............... The results from these experimental studies should be interpreted with caution..................... Infection of humans and mice with Leishmania major in the presTABLE 1....... The efficacy of DENV candidate vaccines was also not influenced by preimmunity to DENV or other flaviviruses (77....... 161)..1 TGF-_ ............with caution. B*07....... Fc_R-mediated infection of murine macrophages with Leishmania amastigotes was required to sustain persistent infection (108.... For instance............................224........................... The role of preimmunity conferred by vaccination against DENV or other flaviviruses in the pathogenesis of DENV infections has been studied in limited numbers of subjects...............................205 HLA class I alleles A*01................... B*51 ..... 166)....................143 G6PD ......... This immunosuppressive effect of Fc_R-mediated infection is in agreement with the decrease in the proliferative responses to mitogen and recall antigens that can be measured during acute DENV infection...

These T cells were shown to recognize a single epitope within the hepatitis C virus NS3 that also cross-reacted with an epitope in the IAV neuraminidase protein. These include the combinations of infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus (VV).and anti-inflammatory cytokines such as IFN-_. TNF-_. 147). In the IAV-MCMV model it was shown that IAV-immune mice challenged with MCMV developed severe consolidating mononuclear pneumonia as a result of increased viral replication in the lungs (41. highly cross-reactive CD8_ T cells with high avidity for the infecting virus are preferentially activated (58. whereas respiratory VV challenge of LCMV-immune mice resulted in recruitment of LCMV-specific CD8_ T cells into the lung. resulting in production of proinflammatory cytokines (154) that may contribute. However. together with the CD8_ T-cell response. evidence exists that sequential infection with different DENV serotypes may also alter the cytokine response of cross-reactive CD4_ T cells. The majority of these cross-reactive T cells produce high concentrations of pro. This could explain the variability seen in disease outcome upon secondary infection with heterologous DENV. During the acute phase of a secondary infection of humans with heterologous DENV. This phenomenon has also been described for LCMV in mice (110). cross-reactive epitopes preferentially reactivate the larger number of memory T cells against the priming virus more effectively than they activate naïve T cells. 209). has been called original antigenic sin (OAS). to a detrimental . as well as influenza A virus (IAV) and murine cytomegalovirus (MCMV) (209). However. These findings suggest that cross-reactive memory T cells can modify the primary immune response and modulate the immunopathologic response to subsequent infection with other pathogens. in accordance to what has been described for several other systems. One example of cross-reactivity leading to disease in humans has also been described (250. or other soluble factors that affect vascular permeability. IL-6.has been shown to cause pathology. 99). Delayed virus clearance would prolong activation of such crossreactive CD8_ T cells. Other studies have also suggested that epitopes can regulate the level of proinflammatory cytokines produced by T cells (146. The authors of those studies reported two cases of fulminant hepatitis C virus infection associated with an unusually high frequency of CD8_ T cells. but it is not clear whether cells die as a result of activation-induced cell death or whether apoptosis is selectively induced by cross-reactive epitopes. low-avidity cross-reactive CD8_ T cells would be preferentially expanded (165. 166). causing bronchiolitis obliterans (40). only a very small subset of cross-reactive memory T cells will be stimulated to expand because of a narrowing TCR repertoire. These crossreactive T cells react differently to the heterologous epitopes than to homologous epitopes by producing high levels of proinflammatory cytokines. but they lose their cytolytic activity. Alternatively. due to the increased frequency and higher activation state of memory cells. it is possible that during a heterologous DENV infection. During a secondary infection with a heterologous serotype. Much less is known about the CD4_ T-cell response during DENV infection. This narrowing of the TCR repertoire in combination with the fact that each individual has a unique TCR specificity (private TCR [52. and IL-13 but somewhat lower levels of IL-10. which then results in the production of high levels of cytokines such as TNF-_. peripheral VV infection of LCMV-immune mice resulted in immune-mediated panniculitis (211). 260). In one study. The phenomenon where cross-reactive memory T cells for the primary infecting virus are more efficiently activated. 107]) would result in dominant responses that are unique for individuals. These high-avidity cross-reactive CD8_ T cells die through apoptosis.

128. the laboratory tests used to measure cytokines. thrombopoietin. More specifically designed studies are needed to dissect the relationships between levels of several cytokines in the pulmonary (pleural fluid) and peritoneal (ascites) regions compared to plasma or serum in severe DENV infections. These discrepancies are attributed mainly to the study design and experimental setup. 169. 44.cytokine release. 71. hemophagocytic syndrome in fulminant virus infections or autoimmune diseases as well as macrophage activation syndrome in hematopoietic cell transplantation has been associated with excessive cytokine production (127. Several studies have shown that concentrations of multiple cytokines and other mediators. tissue factor (TF). 2009 DENGUE VIRUS PATHOGENESIS 569 bers of nonprotective T cells result in a ―storm‖ of inflammatory cytokines and other mediators. 32. TNF-_. IL-18. 115. leading to the increased plasma leakage characteristic of DHF/DSS. hemophagocytic syndrome has been proposed as a cause of the multiorgan dysfunction observed in patients with confirmed H5N1 fatal infections (247. Other mediators and soluble factors found to be increased in severe disease include vascular endothelial growth factor (VEGF). as well as soluble receptors. Analyses of several studies reveal conflicting results. 103. soluble ICAM-1. H5N1 causes fulminant disease in humans. 29. Infection of humans and animals with seasonal IAV (H1N1 or H3N2) indicated that levels of cytokines and chemokines were much higher locally. In contrast. and this may explain some of the discrepant results. 88). 129). both locally and systemically (54a. Furthermore. IL-10. 46. resulting in different vascular permeability patterns. Soluble Factors It is strongly believed by many scientists studying dengue pathogenesis that a high viral load and activation of high numVOL. and IFN-_ have been found in patients with severe DENV infections. plasminogen activator inhibitor 1 (PAI-1). as some studies report increased levels of plasma cytokines while others do not. 268). IL-6. granulocyte-macrophage colony-stimulating factor. 193. soluble vascular cell adhesion molecule 1 (VCAM-1). 130. The production and actions of cytokines are thus critically dependent on the context in which they occur. Some evidence to support a role for cytokines comes from . than in plasma or serum (68. In this case disease severity correlates strongly with cytokine levels. monocyte chemoattractant protein 1 (MCP-1). von Willebrand factor antigen. and the statistical tests applied for the analyses of the results. 172. in particular in patients with DSS (10. 26. 153. Higher plasma levels of IL-1_. 229). TGF-1_. are significantly increased during severe dengue infections (reviewed in reference 15). IL-7. 183. either alone or in combination. IL-8. 192. the functional changes induced in EC that are associated with the increased plasma leakage. 22. IL-2. Notably. 27. and adults infected with different DENV serotypes. 23. These studies analyzed samples from infants. It is reasonable to assume that synergistic interactions between these cytokines will occur. 236). children. at the site of infection. and tissue plasminogen activator (23. It is conceivable that differences in viral replication and damage to selective EC in vivo may account for a differential cytokine profile. One of the most daunting challenges in DENV research is the identification of soluble factors that can mediate. 223. characterized by diffuse alveolar damage and progression to multiorgan dysfunction. IL-13. IL-4. thrombomodulin. 227). For instance. the time of sampling during infection is difficult to standardize. 194. macrophage migration inhibitory factor. E-selectin. The observation that plasma leakage occurs mainly in the pulmonary and peritoneal cavities justifies the question whether levels of cytokines and mediators in plasma indeed reflect concentrations in different compartments.

together with experiments showing that TNF-_ is capable of increasing EC permeability in vitro (55). IFN-_.. The biological roles of some cytokines and soluble factors and the implication in the development of hemorrhage have been inferred and are summarized in Table 2. IL-13 downregulates expression of proinflammatory cytokines IL-1. making it difficult to explain DHF/DSS pathogenesis on the basis of a single cytokine. IL-6. IL-2 plays a central role in the regulation of the immune response.e. High levels of IL-18 may be associated with neutropenia. IL-8 has an effect on the expression of adhesion molecules such as ICAM-1 and VCAM-1. the lack of one specific cytokine may be compensated for by another cytokine with overlapping activities). with peak amounts measured in DHF/DSS cases (2. and IL-12. IL-6 is a major mediator of fever and acute-phase reactions and is produced by macrophages and activated EC. Clearly. and DC. in one study a positive correlation between soluble TNF-_ concentrations and thrombocytopenia was found (23). IL-18 is a type 1 cytokine. In a mouse model of DENV-induced hemorrhage. CLIN. stimulates synthesis of IFN-_ and TNF-_. macrophages. thrombocytopenia.and P-selectins) on EC. Interestingly. and IL-8 in vitro (138). whereas TNF-_ and VEGF act synergistically to induce expression of TF on EC (216). high levels of TNF-_ in tissues correlated with EC apoptosis and hemorrhage (39). 132) and may modulate the activation of coagulation. 217). IL-18 upregulates expression of adhesion molecules (E. TNF-_ has a direct effect on production of IL-6 and thus an indirect effect on coagulation and fibrinolysis. EC produce MCP-1. 162). pathology is mediated via direct lysis of infected cells by TNF-_. In addition. In vitro. For instance. Plasma levels of IL-10 were shown to correlate with platelet decay in DENV-infected patients (10. Furthermore. DENV-infected cells have been shown to produce MMP-9. REV. the TNF-_308A allele. is more commonly found in DHF patients (66). Furthermore. and its receptor is expressed on vascular EC. IL-13 is a pleiotropic type 2 cytokine. It is worth noting that in most models of immunopathology. there is a substantial redundancy between cytokines (i. CD4_ T cells have been shown to produce a unique cytokine called the cytotoxic factor. IL-6 and IL-8 mediate derangement of coagulation and fibrinolysis. 570 MARTINA ET AL. It is more likely that multiple cytokines contribute . IL-4.animal models of increased vascular permeability and hemorrhage during DENV infections (39. In the presence of anti-NS1 antibodies. TNF-_. These observations. and/or IL-10 (91). IL-6. which may contribute to a procoagulant state (167). which leads to overproduction of the cytokine. The validity of these observations has to be confirmed by independent experiments. monocytic cells (47. T cells interacting with DENV-infected cells may also produce TNF-_. and elevated levels of liver enzymes. and may damage the integrity of EC. and has a strong proinflammatory activity. Furthermore. several in vitro experiments have demonstrated high levels of cytokines in culture supernatants of DENV-infected (primary) DC (20). The cytokines TNF-_ and IL-10 are of particular interest. IL-8. IL-6. IL-13 is a potent stimulator of matrix metalloproteinase 9 (MMP-9) and cathepsins and plays important roles in the pathogenesis of emphysema in animal models of respiratory infections. IL-1_. which increases vascular permeability in vitro (145). produced mainly by monocytes. and IL-10 levels have been shown to be high in sera of DENVinfected mice (6). MICROBIOL. and EC (11). MCP-1 causes EC tight-junction openings in vitro (231) and elevates endothelial permeability changes in vivo (265). and it has been shown that CD8_ T-cell cytotoxicity can be mediated exclusively by TNF-_. 37). as it induces potent proliferation of T cells and to a lesser extent of B cells. suggest its possible role in pathogenesis of DHF. During DENV infection.

. Upon inoculation of DENV into the dermis...... pathology characteristic of DHF/DSS are also essential for efficient viral clearance.... IL-6.... IL-8. VEGF stimulates expression of .... which results in platelet aggregation....... NO ....... it is reasonable to assume that cytokines and other soluble mediators of the functional..... and VE-cadherin content... TNF-_ upregulates expression of TF on monocytes and EC and downregulates expression of thrombomodulin on EC. TNF-_ enhances expression of NO and mediates activation-induced death of T cells....C3a activates platelets and enhances their activation and adhesion properties... IL-6.......... and immune modulating activity.. antimicrobial.............. It enhances vasodilatation and formation of edema..... THE INTERGRATED VIEW The mechanisms leading to the severe manifestations of DENV infections are still not completely understood but are likely to be multifactorial (Fig....... is a potent inducer of fever. claudins........ C4b. Maintenance of the EC barrier requires a basal level of NO............... Early in infection.. Thrombin activates EC and increases EC permeability.......... EC........ Activated platelets also secrete soluble CD40 ligand..... Activated platelets release several soluble factors with inflammatory................... Activation of the coagulation system results in increased expression of IL-6 and IL-8 by monocytes....... TGF-_ increases expression of TF on EC and upregulates expression and release of PAI-1.........Thrombin is thought to act near the site at which it is produced...... and TF... Thrombin converts circulating fibrinogen to fibrin and triggers platelet activation................. while at high concentrations it induces apoptosis. C3a and C5a... At low concentrations it protects cells from apoptosis.................IL-10 is produced by monocytes and regulatory T helper cells and may cause platelet decay.. VCAM-1 promotes adhesion of monocytes to the endothelium... 1)..... However. it may upregulate TNF-_ production or downregulate TNF-receptors................TNF-_ in a potent activator of EC and enhances capillary permeability...NO has a multifaceted role in inflammatory reactions.............................TGF-_ may act as a proinflammatory or anti-inflammatory cytokine. melanocyte-stimulating hormone.. IL-10 .. causing enhanced chemokine release and upregulation of VCAM-1.. and hepatocytes. Upon activation... depending on its concentration..... Activated platelets are also involved in C3 cleavage.... Langerhans cells and keratinocytes will primarily be infected........ IL-6 ....... It also activates the fibrinolysis system.......... later in infection....... which cleaves C3 and C5 to C3a/b and C5a/b.. NO downregulates expression of MHC class II and suppresses expansion of Th1 cells. low levels of TGF-_ may trigger secretion of IL-1 and TNF-_.............. TGF-_.. Depending on its concentration.. and it has therefore been implicated in peripheral T-cell deletion....... the pituitary gland to produce antiinflammatory mediators such as endorphins..........Together with other proinflammatory cytokines..... IL-6 potentiates the coagulation cascade............ adhesion molecules...... and adrenocorticotropic hormone.................................... such as MMP-9...... all of which are components of EC junctions.......... together with IL-1..... and TNF-_.......... Thrombin also inhibits IL-12 production by mononuclear cells. C5a enhances blood thrombogenicity by upregulating TF and PAI-1 expression on various cell types............. TNF-_. IL-1 increases the expression of TF on EC and suppresses the cell surface anticoagulant activity of EC.. leading to plasma leakage and edema formation.......... It can downregulate production of TNF-_ and TNF receptors.............. The virus subsequently spreads via the blood (primary viremia) TABLE 2.......... C5a stimulates monocytes to produce IL-1. It upregulates TNF-_ production in monocytes..... Thrombin is chemotactic for monocytes and is mitogenic for lymphocytes and mesenchymal cells...... The cytokine downregulates the inflammatory response and creates a proviral survival milieu. IL-10 promotes OAS by inhibiting development of effector T cells to new epitopes. IL-1 ..... The genetic background of the host influences the way that the immune response reacts to DENV infection............. EC damage in the liver may elevate systemic concentrations.......... respectively........ chemokines........... Summary of soluble factors that are or are likely to be associated with development of DHF/DSS Soluble factor Biological function in relation to pathogenesis Thrombin .....VEGF is a key driver of vascular permeability.. It reduces EC occludins. VEGF.... The fact that DSS patients recover extremely rapidly after appropriate fluid therapy suggests that cytokines do not cause tissue destruction like in many immunopathology models but rather cause a reversible EC dysfunction.. which can induce EC to produce reactive oxygen species.... IL-10 also inhibits the expression of TF and inhibits fibrinolysis.. which induces activation of the classical complement pathway........ as a consequence....IL-8 is a chemokine that is abundantly produced by monocytes...IL-1_ is major mediator of platelet-induced activation of EC............... the cytokine inhibits the Th1 response and enhances production of Th2 cytokines such as IL10.................. Activation of these complement factors is enhanced by thrombin.... while the APC-PS anticoagulation pathway downregulates production of IL-8 by EC.... which enhances EC permeability.... IL-8 ... and to a lesser degree the morphological. Thrombin can stimulate IL-10 production by monocytes..... Apart from any other considerations.. IL-1 stimulates the hypothalamus and.simultaneously in a complex way to the development of DHF/ DSS......C4b binds to protein S and thereby inhibit the anticoagulant properties of activated protein C-protein S complexes...... Both a lack of NO and high NO levels destabilize EC junctions.

In the context of certain HLA haplotypes. Essentially. Only a few studies have studied host genetics with regard to the severity of DENV infection. MICROBIOL. infection of macrophages. and liver cells. a high viral load overstimulates both low. and IL-18. Furthermore. DISCUSSION Here we review and discuss the plethora of hypotheses about DHF and DSS pathogenesis presented in the literature. When IgM antibodies that crossreact with EC. processes leading to the indicated event. VOL. cross-reactive T cells delay virus clearance. and a normal number of functioning platelets is necessary to maintain vascular stability. and E-selectin in EC. and macrophages. Black arrows. and together they harbor multiple elements that collectively may explain most of the phenomena observed in the multiple presentations of DENV infection. A high viral load in blood and possibly viral tropism for EC. 22. monocytes. This eventually results in complex and variable disease outcomes. collectively determine the viral load measured in blood. and gastrointestinal mucosal bleeding (170). and metabolomics). many of which still remain to be identified. In addition. involving both viral and host factors. based on an integrated view of the data presented (see section The Integrated View in the text). these high levels of soluble factors. hemopoiesis is suppressed. VCAM-1. colored boxes with white centers. Necrosis results in release of toxic products. Each event will ultimately affect the EC or the hemostatic system (purple arrows). clinically manifested as petechiae. and plasmin are produced. clinically significant genetic variations consist of single-nucleotide polymorphisms within genes that affect disease pathways. and platelet dysfunction may result in increased capillary fragility. proteomics. 2009 DENGUE VIRUS PATHOGENESIS 571 and infects tissue macrophages in several organs. hepatocytes. Platelets interact closely with EC. The pathogenesis of both DHF grades I/II and DSS is complicated and multifactorial. and EC influences the FIG. REV. However. which is characteristic of DHF. 572 MARTINA ET AL. IL-8. Many polymorphisms have small and independent effects on disease outcome and often act in concert with other polymorphisms and environmental risk factors (24). The replication efficiency of DENV in DC. the loop that results in increased vascular permeability and coagulopathy is amplified.and high-avidity cross-reactive T cells. DHF. induce changes in EC leading to the coagulopathy and plasma leakage characteristic of DSS. singlenucleotide . CLIN. It may be questioned whether factors that explain the pathogenesis of DHF and DSS in all patients do exist. Most commonly. pathological events. Ultimately. 1.ICAM-1. Genetic predisposition may have a significant effect on disease outcome. This viral load represents an important risk factor for development of severe disease. Table 3 addresses major challenges to the hypotheses described in this review. Proposed model for the pathogenesis of DF. easy bruising. especially the macrophages in the spleen. Most of these hypotheses are not mutually exclusive. resulting in decreased blood thrombogenicity. necessary and/or sufficient factors have still not been identified. while producing high levels of proinflammatory cytokines and other mediators. IL-10. which activate the coagulation and fibrinolytic systems. At the same time. Infected cells die predominantly through apoptosis and to a lesser extent through necrosis. enhancing IgG antibodies bind heterologous virus during secondary infection and enhance infection of APCs. hemostatic and the immune responses to DENV. platelets. bone marrow stromal cells. severe thrombocytopenia. Studies using a combination of genomics (transcriptomics. as well as its tropism for and replication efficiency in EC. infection stimulates development of specific antibody and cellular immune responses to DENV. Depending on the extent of infection of bone marrow stromal cells and the levels of IL-6. thereby contributing to the increased viral load that is seen during secondary viremia in some patients. and DSS.

transient autoimmunity. especially APCs. Increased vascular permeability as a result TABLE 3. cytokines. in DHF/DSS pathogenesis Understanding race. maintenance. 22. are also not associated with EC damage (43. the pathways to DHF involve both viral and host-specific elements. In this respect. while no generalized edema is seen. plasma leakage is highly restricted to the pleural and peritoneal cavities. ADE. As discussed in this review. .. It is worth noting that despite the increased vascular permeability measured in both DHF and DSS patients (16). Bunyaviridae (Hanta virus and Rift Valley virus). the pathogenesis of hemorrhagic diathesis is the result of severe liver damage leading to decreased production of coagulation proteins and albumin. and unbalanced T-cell responses Elucidating the role of DENV proteins. In these cases.and T-cell responses elicited during primary and secondary DENV infections and on pathogenesis Elucidating the role of host gene polymorphism. 2009 DENGUE VIRUS PATHOGENESIS 573 of hypercytokinemia and a reduction of plasma osmotic pressure due to severe liver damage contribute to edema formation. especially NS1 in pathogenesis Understanding the interplay between the hemostatic and the complement systems in DENV infection Elucidating the mechanisms by which innate immunity regulates memory B. chemokines. the involvement of liver and of EC in different organ systems seems to be an important factor in the pathogenesis of dengue. such as FcR.polymorphism genotyping. No specific vascular lesions are found in fatal cases of DENV infections.and T-cell generation. and careful phenotypic disease characterization in well-defined cohorts should be adopted to identify individual molecular markers of DHF/DSS. as is seen in severe cases of Lassa fever (67). especially the private repertoire. etc. Challenges for DENV research Challenge Developing an animal model of dengue disease Understanding the role of several DENV strains and serotypes in DENV tropism in vivo Elucidating the role of intrahost evolution of DENVs in emergence of virulent strains and the role of genetic variants and different serotypes in promoting OAS. (i) In contrast to what is generally believed. and Flaviviridae (yellow fever virus). on evolution of T-cell responses during primary and sequential heterologous DENV infections Understanding the role of OAS in T-cell-mediated immunity in heterologous DENV infections and elucidating the factors that determine occurrence of OAS for T cells and its role in pathogenesis Identifying soluble factors that are necessary or sufficient to induce endothelial cell dysfunction and coagulopathy seen in DHF/DSS Identifying critical components of tight junctions and adherent junctions present in the vascular beds affected during DHF/DSS and elucidating the role that different soluble factors play in expression and functions of the several components of these junctions Investigating the effect of demographic history of infection on the type of B. and activation during primary and secondary DENV infections Elucidating the role of autoimmunity in dengue pathogenesis Identifying serotype-specific linear and conformational B-cell epitopes and understanding their role in primary and anamnestic B-cell responses Understanding the role of DENV immune complexes in the signaling network within target cells. Filoviridae (Ebola virus and Marburg virus). such as viruses belonging to the families Arenaviridae (Junin virus and Lassa virus). and how it influences virus replication and priming of immune responses Elucidating the role of the T-helper and T-cytotoxic cell repertoire.and age-dependent susceptibility to severe DENV infection VOL. Viruses known to cause hemorrhagic fever. In addition. 70). The following points can be summarized. it is of paramount importance to understand how EC lining the thoracic and peritoneal cavities are affected.

The pathogenesis of mild hemorrhages seen in DF and DHF grades I/II may be explained by increased capillary fragility as a result of thrombocytopenia or platelet dysfunction. Most mediators that increase vascular permeability affect the organization of the adherens junctions (AJ). however. virus infection of EC. and Jarish Herxheimer . High concentrations of cytokines such TNF-_.replication of most of these viruses in the adrenal gland contributes to hypotension and sodium loss. and IL-8 have been implicated in capillary leakage and development of hypovolemic shock in patients with anaphylaxis. meningococcal sepsis. 62). Platelets play a role in maintaining the integrity of AJ by constitutively releasing an array of factors such as plateletactivating factor and sphingosine-1-phosphate. lose their cytolytic activity. IL-6. which are released as a result of fluid shear stress (5). the WHO case definition has mainly a clinical diagnostic purpose and is not an appropriate selection criterion for pathogenesis studies. The role that preexisting immunity to other flaviviruses plays in the development of severe dengue should be investigated. The shock syndrome associated with DSS. which collectively result in hypovolemic shock. It is crucial to study the pleural fluid in order to understand the pathophysiological cause of plasma leakage and why it is restricted to or more pronounced in thoracic and peritoneal areas. their concentrations are also elevated in other viral infections without resulting in plasma leakage. (iv) Antibody-mediated enhancement of infection either results in a high viral load or represents the link to type 2 cytokine responses. 257). and high concentrations of cytokines that disrupt vascular integrity (54. (v) In some viral systems. cross-reactive CD8_ T-cell responses are involved in the development of pathological changes during secondary infection with a related but heterologous virus. causing retraction of EC and opening of intercellular gaps. while producing high levels of proinflammatory cytokines and other mediators. however. which are rich in AJ (170). with an increased tendency of bleeding upon bruising. as is exemplified by the fact that internalization of VE-caherin or phosphorylation of AJ proteins reduces junction stability without the opening of intercellular gaps (4. (vi) Soluble host factors seem to be central in the pathogenesis of both DHF grades I/II and DSS. (ii) Hemorrhagic manifestations as seen in DF and DHF grades I/II are usually mild and manifested as petechiae disseminated in the skin. Weakness of the junctions is not reflected by morphological changes. As mentioned before. interruption of platelet-EC interaction by severe thrombocytopenia or platelet dysfunction may lead to increased vascular fragility. (ii) increased manifestations of bleeding or tendencies for bleeding. or (iii) plasma leakage as measured by sonography and hemoconcentration. a complex network of adhesion proteins that are linked to intracellular cytoskeleton (54). These manifestations are found early after onset of fever and coincide with the window of viremia and degree of thrombocytopenia (121). Therefore. resulting in vascular fragility. (iii) Several studies have shown that plasma leakage occurs before defervescence or hemoconcentration. Although several of these have been associated with severe disease. Alternatively. DENV cross-reactive T cells. Pathogenesis studies should be designed to understand the differences between (i) no bleeding tendencies. 170. and it is of paramount importance to understand how the EC lining the thoracic and peritoneal cavities are affected. resulting in hemorrhages or increased tendencies for hemorrhages. is unique to DENV infection. It is noteworthy that the major anatomical sites of bleeding in patients with severe thrombocytopenia are the intercellular gaps in the postcapillary venules. the stability of the junctions may be weakened.

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both at Utrecht University (The Netherlands). During the past 10 years. He and his team have identified more than a dozen ―new‖ viruses (e.. authored about 800 academic articles. and held several editorial positions. .D. She obtained her Ph. Albert Osterhaus graduated as a veterinarian in 1974 and obtained a Ph.D. created biotech companies. human metapneumovirus and a novel human coronavirus) and proved that the severe acute respiratory syndrome coronavirus is the cause of severe acute respiratory syndrome. He is particularly interested in viruses that affect animals and humans and cross species barriers. her research focuses on virulence factors of vector-borne viruses. being involved in the characterization of immune responses and development of animal models and vaccines. Recently.Infectious Diseases in Leicester (United Kingdom). he became Professor of Environmental Virology at Utrecht University and Professor/ Head of Department of Virology at Erasmus MC in Rotterdam in 1992 and 1994. His studies focused on virus outbreaks in wildlife. After working at the National Institute of Health of The Netherlands. and antiviral drugs. supervisor for more than 40 students. natural and vaccineinduced immune responses.D. focusing on the identification of new respiratory pathogens.g. As a junior postdoc she joined the ―Virus Discovery‖ team at the same department. Currently. she joined the ―Emerging Viruses‖ team of the same department. respectively. degree at the Department of Virology at Erasmus Medical Center in Rotterdam (The Netherlands) in 2007 studying dengue virus infections in humans and nonhuman primates. degree in virology in 1978. with a main focus on dengue viruses. He acted as Ph. mechanisms of transmission and pathogenesis of zoonotic viruses. she has gained broad experience working on emerging pathogens.

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