Gavin Screaton

Imperial College London, Londinium, England, United Kingdom

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Publications (93)808.7 Total impact

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    Sophie Yacoub · Juthathip Mongkolsapaya · Gavin Screaton

    Preview · Article · Jan 2016 · F1000 Research
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    ABSTRACT: Dengue virus poses a major threat to global public health: two-thirds of the world's population is now at risk from infection by this mosquito-borne virus. Dengue virus causes a range of diseases with a small proportion of infected patients developing severe plasma leakage that leads to dengue shock syndrome, organ impairment and bleeding. Infection with one of the four viral serotypes results in the development of homotypic immunity to that serotype. However, subsequent infection with a different serotype is associated with an increased risk of developing severe disease, which has led to the suggestion that severe disease is triggered by immunopathology. This Review outlines recent advances in the understanding of immunopathology, vaccine development and human monoclonal antibodies produced against dengue virus.
    No preview · Article · Nov 2015 · Nature reviews. Immunology

  • No preview · Article · Sep 2015 · Tropical Medicine & International Health
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    ABSTRACT: Dengue infection can result in a wide spectrum of disease. The defining feature of severe disease is increased capillary permeability, which can lead to hypovolaemic shock. Microvascular and endothelial dysfunction might underlie hypovolaemic shock, but they have not been assessed clinically. We aimed to investigate the use of microvascular assessment as a prognostic method in dengue. This is an ongoing prospective observational study that aims to recruit 300 participants: children over the age of 3 years and adults presenting to two outpatient departments in Vietnam with fever of less than 72 h duration and suspected dengue, and patients admitted to hospital with warning signs or severe disease. Participants are being clinically assessed daily for 6 days, and 2 weeks later. Microvascular imaging using sublingual sidestream darkfield imaging (SDF) and endothelial function testing using peripheral artery tonometry are being performed at enrolment, defervescence, and follow-up FINDINGS: To date, 167 patients have been recruited (92 outpatient arm, 75 inpatient arm, median age 27 years [IQR 21-33], 78 male [47%]). Dengue has been confirmed in 67 individuals in the outpatient arm, of whom 29 (43%) developed warning signs, three (4%) developed severe disease, and 35 had uncomplicated dengue; the other 25 outpatients (27%) were diagnosed as other febrile illness. At enrolment, the reactive hyperaemic index, a marker of endothelial function, was lowest in the patients who went on to develop severe dengue (median 1·54, IQR 1·36-1·77) followed by those who developed warning signs (1·78, 1·43-2·36) and then uncomplicated dengue (2·18, 1·65-2·24). Initial SDF results showed a lower proportion of perfused vessels and mean flow index during the febrile phase of dengue compared with follow-up, and were worst in the severe group at defervescence. This study of vascular function at serial timepoints in dengue is, to our knowledge, the first and most comprehensive. Our preliminary results suggest that microvascular and endothelial dysfunction are associated with severity of dengue, and occur before the appearance of severe clinical manifestations. These techniques might be useful in risk prediction in dengue. A limitation is that a formal sample size could not be calculated because no previous microvascular data in dengue exist. Wellcome Trust. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Feb 2015 · The Lancet
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    ABSTRACT: Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.
    No preview · Article · Jan 2015 · Nature
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    ABSTRACT: Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.
    Full-text · Article · Dec 2014 · Nature Immunology
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    ABSTRACT: Dengue virus (DENV) is the leading cause of mosquito-borne viral illness and death in humans. Like many viruses, DENV has evolved potent mechanisms that abolish the antiviral response within infected cells. Nevertheless, several in vivo studies have demonstrated a key role of the innate immune response in controlling DENV infection and disease progression. Here, we report that sensing of DENV infected cells by plasmacytoid dendritic cells (pDCs) triggers a robust TLR7-dependent production of IFNα, concomitant with additional antiviral responses, including inflammatory cytokine secretion and pDC maturation. We demonstrate that unlike the efficient cell-free transmission of viral infectivity, pDC activation depends on cell-to-cell contact, a feature observed for various cell types and primary cells infected by DENV, as well as West Nile virus, another member of the Flavivirus genus. We show that the sensing of DENV infected cells by pDCs requires viral envelope protein-dependent secretion and transmission of viral RNA. Consistently with the cell-to-cell sensing-dependent pDC activation, we found that DENV structural components are clustered at the interface between pDCs and infected cells. The actin cytoskeleton is pivotal for both this clustering at the contacts and pDC activation, suggesting that this structural network likely contributes to the transmission of viral components to the pDCs. Due to an evolutionarily conserved suboptimal cleavage of the precursor membrane protein (prM), DENV infected cells release uncleaved prM containing-immature particles, which are deficient for membrane fusion function. We demonstrate that cells releasing immature particles trigger pDC IFN response more potently than cells producing fusion-competent mature virus. Altogether, our results imply that immature particles, as a carrier to endolysosome-localized TLR7 sensor, may contribute to regulate the progression of dengue disease by eliciting a strong innate response.
    Full-text · Article · Oct 2014 · PLoS Pathogens
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    ABSTRACT: Background Dengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection. Methods Blood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured. Results iNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated. Conclusion iNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.
    Full-text · Article · Jun 2014 · PLoS Neglected Tropical Diseases
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    ABSTRACT: Dengue is one of the most important emerging viral diseases globally. The majority of symptomatic infections result in a relatively benign disease course. However, a small proportion of patients develop severe clinical manifestations, including bleeding, organ impairment, and endothelial dysfunction with increased capillary permeability causing hypovolaemic shock that can lead to cardiovascular collapse. Evidence is increasing that dengue can also cause myocardial impairment, arrhythmias and, occasionally, fulminant myocarditis. No antiviral agents or vaccines are licensed for dengue, and treatment remains supportive with judicious fluid replacement for patients with severe disease. Defining the role of cardiac dysfunction in the haemodynamic compromise of severe dengue has potentially important management implications. In this Review, we will outline the current understanding of the cardiovascular manifestations of dengue, including myocardial and vascular involvement, and conclude with a discussion of the available therapeutic options and potential future research directions.
    Full-text · Article · Apr 2014 · Nature Reviews Cardiology

  • No preview · Chapter · Feb 2014
  • G. Screaton · J. Mongkolsapaya

    No preview · Article · Jan 2014
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    Full-text · Article · Dec 2013 · PLoS Neglected Tropical Diseases
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    Full-text · Article · Dec 2013
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    ABSTRACT: Dengue is a rapidly spreading vector-borne disease estimated to infect 400 million people worldwide. To date, there are no licensed treatments or vaccines. The last few years have seen significant developments in dengue control strategies. In this review, we will address four key areas: vaccines, vector control, antivirals and immunotherapeutics. The first generation of dengue vaccines is able to induce good serological responses in test individuals. However, the recent Sanofi-Pasteur trial in Thailand found that a good serological response did not correlate with clinical protection. This trial did not demonstrate an increase in cases of severe disease following immunization, suggesting that concerns over vaccine-related immune enhancement may have been overcome. The bacterium Wolbachia appears to control dengue proliferation in Aedes mosquitoes, and field studies are underway. A large number of antivirals are in early-stage development and may prove useful in epidemics. Monoclonal antibodies have been postulated to have a clinical role. Whether their clinical application is feasible has yet to be seen. Marked improvements in our knowledge of dengue have been made over the recent years. Sadly, clinical application remains some years away.
    No preview · Article · Oct 2013 · Current Opinion in Infectious Diseases
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    ABSTRACT: Here we present an approach that advances the throughput of a genetic analysis of a positive-sense RNA virus by simplifying virus construction. It enabled comprehensive dissection of a complex, multigene phenotype through rapid derivation of a large number of chimeric viruses and construction of a mutant library directly from a virus pool. The versatility of the approach described here expands the applicability of diverse genetic approaches to study these viruses.
    Full-text · Article · Sep 2013 · Journal of Virology
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    ABSTRACT: The envelope (E) protein of dengue virus (DENV) is the major target of neutralizing antibodies (Abs) and vaccine development. Previous studies of human dengue-immune sera reported a significant proportion of anti-E Abs were cross-reactive to all four DENV serotypes and to one or more other flaviviruses, known as group-reactive (GR). Based on the studies of mouse anti-E monoclonal antibodies (mAbs), GR mAbs were non- or weakly neutralizing compared with type-specific mAbs; GR response was thus not regarded as important for vaccine strategy. We investigated the epitopes, binding avidity and neutralization potency of 32 human GR anti-E mAbs. In addition to fusion loop (FL) residues in E protein domain II, human GR mAbs recognized an epitope involving both FL and bc loop residues in domain II. The neutralization potency and binding avidity of GR mAbs derived from secondary DENV infection were stronger than those derived from primary infection. GR mAbs derived from primary DENV infection primarily block attachment, whereas those derived from secondary infection block DENV at post-attachment. Analysis of repertoire of anti-E mAbs dereived from patients with primary DENV infection revealed that the majority were GR, low avidity and weakly neutralizing, whereas those from secondary infection were primarily GR, high avidity and potent neutralizing. Our findings suggest the weakly neutralizing GR anti-E Abs generated from primary DENV infection become potent neutralizing against four serotypes after secondary infection. The observations that the dengue immune status of host affects the quality of cross-reactive Abs generated have implications for new strategies of DENV vaccine.
    Full-text · Article · Sep 2013 · Journal of Virology
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    ABSTRACT: Dengue disease is a mosquito-borne infection caused by Dengue virus. Infection may be asymptomatic or variably manifest as mild Dengue fever (DF) to the most severe form, Dengue hemorrhagic fever (DHF). Mechanisms that influence disease severity are not understood. Complement, an integral component of the immune system, is activated during Dengue infection and the degree of activation increases with disease severity. Activation of the complement alternative pathway is influenced by polymorphisms within activation (factor B rs12614/rs641153, C3 rs2230199) and regulatory (complement factor H [CFH] rs800292) proteins, collectively termed a complotype. Here, we tested the hypothesis that the complotype influences disease severity during secondary Dengue infection. In addition to the complotype, we also assessed two other disease-associated CFH polymorphisms (rs1061170, rs3753394) and a structural polymorphism within the CFH protein family. We did not detect any significant association between the examined polymorphisms and Dengue infection severity in the Thai population. However, the minor allele frequencies of the factor B and C3 polymorphisms were less than 10% so our study was not sufficiently powered to detect an association at these loci. We were also unable to detect a direct interaction between CFH and Dengue NS1 using both recombinant NS1 and DV2-infected culture supernatants. We conclude that the complotype does not influence secondary Dengue infection severity in the Thai population.
    Preview · Article · Aug 2013 · Clinical & Experimental Immunology
  • Sophie Yacoub · Juthathip Mongkolsapaya · Gavin Screaton
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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.
    No preview · Article · Feb 2013 · Current Opinion in Infectious Diseases
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    Demin Li · An Hong · Qiong Lu · George F Gao · Boquan Jin · Gavin R Screaton · Xiao-Ning Xu
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    ABSTRACT: Unlabelled: Humans express four MHC-like CD1 molecules CD1a, b, c and d that are capable of presenting a wide variety of self or foreign lipid antigens to T cells. Much progress has been made in elucidating the function of CD1d-restricted NKT cells in both innate and adaptive immune responses. However, knowledge of the other CD1 molecules is less well defined in terms of lipid presentation and immune regulation. We have previously shown that immunoglobulin-like transcript 4 (ILT4) binds to CD1d and inhibits its recognition by NKT cells. In this study, we show that CD1c can also interact specifically with ILT4 with a higher affinity than that of CD1d. Furthermore, changes in CD1c expression seem to modulate CD1d function; up-regulation of CD1c enhances NKT recognition of CD1d and down-regulation reduces CD1d recognition. We propose that CD1c can act as a sink for the inhibitory receptor ILT4: when CD1c is up-regulated, ILT4 is recruited to CD1c, thus reducing the inhibitory effect of ILT4 on CD1d recognition. Consequently, CD1c could be a potential target for modulating NKT activity. Keywords: NKT, CD1d, CD1c, ILT4, antigen presentation.
    Preview · Article · Aug 2012 · International Immunology
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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).
    No preview · Article · Apr 2012 · British journal of hospital medicine (London, England: 2005)

Publication Stats

6k Citations
808.70 Total Impact Points

Institutions

  • 2004-2015
    • Imperial College London
      • • Division of Infectious Diseases
      • • Department of Medicine
      • • Section of Immunology
      Londinium, England, United Kingdom
  • 2004-2012
    • University of Oxford
      • • Division of Structural Biology (STRUBI)
      • • MRC Human Immunology Unit
      • • Nuffield Department of Clinical Medicine
      Oxford, ENG, United Kingdom
  • 2005-2009
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 1993-2009
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Medicine
      Oxford, England, United Kingdom
  • 1999
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
    • University of California, San Diego
      • Department of Cellular and Molecular Medicine (CMM)
      San Diego, California, United States
  • 1997
    • National Institute for Biological Standards and Control
      Potters Bar, England, United Kingdom