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ABSTRACT: PURPOSE OF REVIEW: Dengue is one of the most rapidly spreading vector-borne diseases in the world, with the incidence increasing 30-fold in the past 50 years. There are currently no licensed treatments or vaccines for dengue. This review covers the recent advances in our understanding of dengue pathogenesis, including host and viral determinants. RECENT FINDINGS: The pathogenesis of severe dengue is thought to be immune-mediated due to the timing of the clinical manifestations and higher incidence in secondary infections with a heterologous serotype. Recent evidence has provided further information of neutralizing versus enhancing monoclonal antibodies and their target epitopes on the dengue virion, which has major implications for vaccine design. The role of T-cell immunopathology has also been advanced with recent evidence of cross-reactive high pro-inflammatory cytokine producing T cells predominating in severe dengue. Recent large genome-wide association studies have identified specific susceptibility loci associated with severe disease. Epidemiological studies have served to define certain at-risk groups and specific viral virulence factors have recently been described. SUMMARY: The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors. Better understanding of the underlying mechanisms leading to severe dengue is crucial if we are to develop prognostic markers, novel diagnostics and therapeutics and ultimately a balanced and safe vaccine.
Current Opinion in Infectious Diseases 02/2013; · 4.93 Impact Factor
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ABSTRACT: Dengue is a flavivirus which is endemic throughout tropical and sub-tropical regions across the globe (Figure 1) (Pinheiro and Corber, 1997). Case reports describe dengue-like illnesses dating back to the late 18th century (Rush, 1789). It now causes disease predominantly in children and adolescents who live in the tropics, and in travellers (Gubler, 1997; Wilder-Smith and Schwartz, 2005).
British journal of hospital medicine (London, England: 2005) 04/2012; 73(4):C60-4. · 0.19 Impact Factor
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ABSTRACT: Dengue virus receptors are relatively poorly characterized, but there has been recent interest in 2 C-type lectin molecules, dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) and its close homologue liver/lymph node-specific ICAM-3-grabbing integrin (L-SIGN), which can both bind dengue and promote infection. In this report we have studied the interaction of dengue viruses produced in insect cells, tumor cell lines, and primary human dendritic cells (DCs) with DC-SIGN and L-SIGN. Virus produced in primary DCs is unable to interact with DC-SIGN but remains infectious for L-SIGN-expressing cells. Skin-resident DCs may thus be a site of initial infection by insect-produced virus, but DCs will likely not participate in large-scale virus replication during dengue infection. These results reveal that differential glycosylation of dengue virus envelope protein is highly dependent on cell state and suggest that studies of virus tropism using virus prepared in insect cells or tumor cell lines should be interpreted with caution.
The Journal of Infectious Diseases 06/2011; 203(12):1775-83. · 6.41 Impact Factor
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ABSTRACT: Dengue infections are increasing at an alarming rate in many tropical and subtropical countries, where epidemics can put health care systems under extreme pressure. The more severe infections lead to dengue hemorrhagic fever (DHF), which can be life threatening. A variety of viral and host factors have been associated with the severity of dengue infections. Because secondary dengue infection is more commonly associated with DHF than primary infections, the acquired immune response to dengue, both B cells and T cells have been implicated. In this study, we set out to study T-cell responses across the entire dengue virus proteome and to see whether these were related to disease severity in a cohort of dengue-infected children from Thailand. Robust responses were observed in most infected individuals against most viral proteins. Responses to NS3 were the most frequent, and there was a very strong association between the magnitude of the response and disease severity. Furthermore, in DHF, cytokine-high CD107a-negative cells predominated.
Proceedings of the National Academy of Sciences 09/2010; 107(39):16922-7. · 9.68 Impact Factor
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Wanwisa Dejnirattisai,
Amonrat Jumnainsong,
Naruthai Onsirisakul,
Patricia Fitton,
Sirijitt Vasanawathana,
Wannee Limpitikul,
Chunya Puttikhunt,
Carolyn Edwards,
Thaneeya Duangchinda,
Sunpetchuda Supasa,
Kriangkrai Chawansuntati,
Prida Malasit,
Juthathip Mongkolsapaya, Gavin Screaton
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ABSTRACT: Dengue virus co-circulates as four serotypes, and sequential infections with more than one serotype are common. One hypothesis for the increased severity seen in secondary infections is antibody-dependent enhancement (ADE) leading to increased replication in Fc receptor-bearing cells. In this study, we have generated a panel of human monoclonal antibodies to dengue virus. Antibodies to the structural precursor-membrane protein (prM) form a major component of the response. These antibodies are highly cross-reactive among the dengue virus serotypes and, even at high concentrations, do not neutralize infection but potently promote ADE. We propose that the partial cleavage of prM from the viral surface reduces the density of antigen available for viral neutralization, leaving dengue viruses susceptible to ADE by antibody to prM, a finding that has implications for future vaccine design.
Science 05/2010; 328(5979):745-8. · 31.20 Impact Factor
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ABSTRACT: It has been widely demonstrated that a quantitative and/or qualitative impairment of regulatory T cells (T(regs)) play a fundamental role in the initiation and persistence of rheumatoid arthritis (RA) in animal models and in patients. In the present work it is demonstrated that partial myeloablation induces a relative expansion of T(regs) that is sufficient to mediate immunological tolerance.
(1) To test the ability of low-intensity myeloablation mediated T(reg) activation to prevent and/or to treat experimental arthritis using the collagen-induced arthritis (CIA) model and (2) to clarify the role of T(reg) in mediating the beneficial effect.
Low-dose irradiation was used before the induction of arthritis or at the onset of disease. The role of T(regs) (CD4CD25forkhead box P3 (FoxP3)(+) cells) and their suppressive activity was assessed by testing their functional activities ex vivo after the treatment and by their in vivo depletion before the treatment.
It was observed that irradiation ameliorated CIA before or after disease induction. T(regs) appear to play a fundamental role in the therapeutic efficacy of irradiation, because the depletion of CD25 or folate receptor (FR)4(+) cells with specific antibodies before the treatment abolished the beneficial effects. The therapeutic efficacy was associated with an increment in the proportion of T(regs) despite the overall reduction in lymphocyte counts. Furthermore, a decline in the percentage of CD4CD25FoxP3(+) T(regs) was associated with disease flare.
In vivo T(reg) expansion is a feasible and effective approach in the treatment of autoimmune diseases.
Annals of the rheumatic diseases 05/2010; 69(8):1519-26. · 8.11 Impact Factor
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ABSTRACT: Severe dengue virus (DV) infections can cause the life-threatening condition dengue hemorrhagic fever, which is characterized by a severe plasma leak, thrombocytopenia, hemorrhage, and, in severe cases, circulatory collapse and death. There is now much evidence that pre-existing immunity to DV can enhance disease when an individual becomes infected on a second or sequential occasion. It has been shown that in contrast to infected dendritic cells (DC), noninfected bystander DC underwent maturation in dengue infection. In this study, we show that TNF-alpha and type I IFN contribute to the maturation of bystander DC, whereas the inhibition of DV-infected DC maturation can be overcome by activated T cells. Furthermore, IFN-gamma-inducible chemokines, CXCL9, 10, and 11 produced by infected DC are greatly amplified in the presence of DV-specific T cells. The chemokine secretion is also enhanced in coculture of HUVEC with either DV-infected DC or activated T cells. Finally, we found a close correlation between the serum level of these three chemokines and disease severity.
The Journal of Immunology 12/2008; 181(9):5865-74. · 5.79 Impact Factor
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Pojchong Chotiyarnwong,
Guillaume B Stewart-Jones,
Michael J Tarry,
Wanwisa Dejnirattisai,
Christian Siebold,
Michael Koch,
David I Stuart,
Karl Harlos,
Prida Malasit, Gavin Screaton,
Juthathip Mongkolsapaya,
E Yvonne Jones
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ABSTRACT: T-cell recognition of the antigenic peptides presented by MHC class I molecules normally triggers protective immune responses, but can result in immune enhancement of disease. Cross-reactive T-cell responses may underlie immunopathology in dengue haemorrhagic fever. To analyze these effects at the molecular level, the functional MHC class I molecule HLA-A*1101 was crystallized bound to six naturally occurring peptide variants from the dengue virus NS3 protein. The crystals contained high levels of solvent and required optimization of the cryoprotectant and dehydration protocols for each complex to yield well ordered diffraction, a process that was facilitated by the use of a free-mounting system.
Acta Crystallographica Section F Structural Biology and Crystallization Communications 06/2007; 63(Pt 5):386-92. · 0.51 Impact Factor
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ABSTRACT: CD4+CD25+ regulatory T cells (Treg) are known to influence T cell responses to tumours. Here we have explored the role of Treg in inhibiting not only adaptive, but also innate immune responses to tumours. To this end we used a Fas ligand (FasL)-expressing melanoma cell line in a mouse model. In this system, innate immunity is sufficient to reject the tumour. All mice depleted of Treg and challenged with FasL-expressing melanoma remained tumour-free. Investigation of the underlying cellular effector mechanisms revealed that depletion of Treg enhanced an NK cell response capable of tumour lysis. Furthermore, this initial innate immune response primed mice to make an effective adaptive immune response leading to complete rejection of challenge with the parental melanoma. Both antigen-specific antibody and CD4+ T cells were implicated in protection via adaptive immunity. We conclude that removal of Treg and vaccination with whole tumour cells expressing FasL activates multiple arms of the immune system, leading to efficient tumour rejection. These findings highlight a novel role for FasL in inducing innate immune responses that are normally inhibited by Treg and uncover an adjuvant effect of FasL that can be used to stimulate tumour immunity after depletion of Treg.
European Journal of Immunology 04/2007; 37(3):758-67. · 5.10 Impact Factor
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Juthathip Mongkolsapaya,
Thaneeya Duangchinda,
Wanwisa Dejnirattisai,
Sirijit Vasanawathana,
Panisadee Avirutnan,
Aroonroong Jairungsri,
Nuanpan Khemnu,
Nattaya Tangthawornchaikul,
Pojchong Chotiyarnwong,
Kanokwan Sae-Jang,
Michael Koch,
Yvonne Jones,
Andrew McMichael,
Xiaoning Xu,
Prida Malasit, Gavin Screaton
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ABSTRACT: Dengue virus infection poses a growing public health and economic burden in a number of tropical and subtropical countries. Dengue circulates as a number of quasispecies, which can be divided by serology into four groups or serotypes. An interesting feature of Dengue, recognized over five decades ago, is that most severe cases that show hemorrhagic fever are not suffering from a primary infection. Instead, they are reinfected with a virus of different serotype. This observation poses considerable problems in vaccine design, and it is therefore imperative to gain a full understanding of the mechanisms underlying this immunological enhancement of disease. In this study, we examined a T cell epitope restricted by HLA-A*24, a major MHC class I allele, in Southeast Asia in a cohort of children admitted to a hospital with acute Dengue infection. The cytokine profiles and the degranulation capacity of T cells generated to this epitope are defined and compared across different viral serotypes. Cross-reactive Dengue-specific T cells seem to show suboptimal degranulation but high cytokine production, which may contribute to the development of the vascular leak characteristic of Dengue hemorrhagic fever.
The Journal of Immunology 04/2006; 176(6):3821-9. · 5.79 Impact Factor
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ABSTRACT: The enhancement of severe disease upon secondary infection makes dengue almost unique among infectious pathogens and presents a serious challenge to vaccine design. Several key observations have been made which shed light onto this phenomenon particularly that antibodies can enhance Fc receptor-dependent uptake of virus into macrophages thereby increasing virus replication. Furthermore there seems to be a relationship between the peak virus load and disease severity. However, a second key feature of dengue is that the life-threatening symptoms do not correlate with the period of high viraemia; instead they occur at a time when the virus load is in steep decline. The coincidence of severe disease manifestations with defervescence and virus control suggests that the symptoms may be a consequence of the immune response to the virus rather than virus induced cytopathology. One of the key elements in the immune response to viruses are T cells which can both secrete a host of inflammatory cytokines and also be directly cytotoxic to infected cells. There are a number of experimental models of T cell-induced immunopathology including in responses to viruses. Particularly interesting in this respect are models of RSV-induced immunopathology, which have direct relevance to vaccine design as a formalin-inactivated vaccine to RSV actually enhanced disease in children when they became naturally infected with RSV, an echo of the disease enhancement seen in dengue. We will present an analysis of CD8+ T cell responses to a number of novel T cell epitopes during dengue infection and also analyse the function and cytokine secretion of these cells. We suggest that an exaggerated and partially misdirected T cell response seen in secondary dengue infection may be part of the complex series of events leading to dengue haemorrhagic fever and shock.
Novartis Foundation symposium 02/2006; 277:164-71; discussion 171-6, 251-3.
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Vera S F Chan,
Kelvin Y K Chan,
Yongxiong Chen,
Leo L M Poon,
Annie N Y Cheung,
Bojian Zheng,
Kwok-Hung Chan,
William Mak,
Hextan Y S Ngan,
Xiaoning Xu, Gavin Screaton,
Paul K H Tam,
Jonathan M Austyn,
Li-Chong Chan,
Shea-Ping Yip,
Malik Peiris,
Ui-Soon Khoo,
Chen-Lung S Lin
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ABSTRACT: Severe acute respiratory syndrome (SARS) is caused by infection of a previously undescribed coronavirus (CoV). L-SIGN, encoded by CLEC4M (also known as CD209L), is a SARS-CoV binding receptor that has polymorphism in its extracellular neck region encoded by the tandem repeat domain in exon 4. Our genetic risk association study shows that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. L-SIGN is expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for L-SIGN, cells homozygous for L-SIGN show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. Thus, homozygosity for L-SIGN plays a protective role during SARS infection.
Nature Genetics 02/2006; 38(1):38-46. · 35.53 Impact Factor
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ABSTRACT: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential therapeutic value against cancers because of its selective cytotoxicity to many transformed, but not normal, cells. The "decoy receptors" TRAIL-R3 (TR3) and TRAIL-R4 (TR4) were believed to negatively regulate TRAIL-induced cytotoxicity by competing for ligand binding with TRAIL-R1 (TR1) and TRAIL-R2 (TR2). Here, we show that inhibition of TRAIL-induced apoptosis by TR4 critically depends on its association with TR2 via the NH(2)-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors. By contrast, ligand binding by TR4 is dispensable for its apoptosis inhibitory function, thereby excluding the possibility that TR4 was a "decoy" to inhibit apoptosis by binding up TRAIL. In primary CD8(+) T cells, which express only TR2 and TR4 and are resistant to TRAIL-induced apoptosis, stimulation with phorbol myristate acetate abrogated the ligand-independent interaction between TR2 and TR4 and enhanced their sensitivity to TRAIL-induced apoptosis. Hence, whereas most TNF receptors normally form only homotrimeric complexes, the preligand assembly domains in TR2 and TR4 permit mixed complex formation as a means to regulate apoptosis induction. We propose that TR4 is a "regulatory" rather than "decoy" receptor that inhibits apoptosis signaling by TRAIL through this previously uncharacterized ligand-independent mechanism.
Proceedings of the National Academy of Sciences 01/2006; 102(50):18099-104. · 9.68 Impact Factor
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ABSTRACT: The multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. We conclude that, through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth.
Proceedings of the National Academy of Sciences 09/2005; 102(31):11017-22. · 9.68 Impact Factor
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Tao Dong,
Guillaume Stewart-Jones,
Nan Chen,
Philippa Easterbrook,
Xiaoning Xu,
Laura Papagno,
Victor Appay,
Michael Weekes,
Chris Conlon,
Celsa Spina,
Susan Little, Gavin Screaton,
Anton van der Merwe,
Douglas D Richman,
Andrew J McMichael,
E Yvonne Jones,
Sarah L Rowland-Jones
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ABSTRACT: HIV-specific cytotoxic T lymphocytes (CTL) are important in controlling HIV replication, but the magnitude of the CTL response does not predict clinical outcome. In four donors with delayed disease progression we identified Vbeta13.2 T cell receptors (TCRs) with very similar and unusually long beta-chain complementarity determining region 3 (CDR3) regions in CTL specific for the immunodominant human histocompatibility leukocyte antigens (HLA)-B8-restricted human immunodeficiency virus-1 (HIV-1) nef epitope, FLKEKGGL (FL8). CTL expressing Vbeta13.2 TCRs tolerate naturally arising viral variants in the FL8 epitope that escape recognition by other CTL. In addition, they expand efficiently in vitro and are resistant to apoptosis, in contrast to FL8-specific CTL using other TCRs. Selection of Vbeta13.2 TCRs by some patients early in the FL8-specific CTL response may be linked with better clinical outcome.
Journal of Experimental Medicine 01/2005; 200(12):1547-57. · 13.85 Impact Factor
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ABSTRACT: CD25+ regulatory T cells comprise 5-10% of CD4+ T cells in naïve mice and have been shown in several in vivo murine models to prevent the induction of autoimmune disease and inflammatory disease. Since T cells, which mediate autoimmunity, can through recognition of self-antigens also target tumour cells, it was postulated that CD25+ regulatory cells would also inhibit the generation of immune responses to rumours. Depletion of these cells using CD25-specific monoclonal antibodies has indeed been shown to promote rejection of several transplantable murine tumour cell lines including melanoma, leukaemia and colorectal carcinoma. Results obtained using these models indicate that in the absence of regulatory cells, CD4+ T cells mediate tumour immunity, although the precise mechanisms through which these cells result in tumour rejection have not yet been elucidated. The target antigens recognized by these CD4+ T cells have also not yet been identified. Immunization of mice with tumour cells in the absence of CD25+ regulatory cells does, however, induce immunity against a variety of different tumour cell lines indicating that the target antigen(s) are shared amongst tumours of distinct histological origins. Since CD25+ regulatory cells have been identified in humans, the possibility that the cells inhibit immune responses to shared rejection antigens expressed by human tumours is worthy of investigation.
Novartis Foundation symposium 02/2004; 256:149-52; discussion 152-7, 259-69.
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Juthathip Mongkolsapaya,
Wanwisa Dejnirattisai,
Xiao-ning Xu,
Sirijitt Vasanawathana,
Nattaya Tangthawornchaikul,
Aroonrung Chairunsri,
Siraporn Sawasdivorn,
Thaneeya Duangchinda,
Tao Dong,
Sarah Rowland-Jones,
Pa-thai Yenchitsomanus,
Andrew McMichael,
Prida Malasit, Gavin Screaton
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ABSTRACT: Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus-specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.
Nature Medicine 08/2003; 9(7):921-7. · 22.46 Impact Factor
