High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection

Tao Dong, Edward Moran, Nguyen Van Vinh Chau, Cameron Simmons, Kerstin Luhn, Yanchun Peng, Bridget Wills, Nguyen Phuong Dung, Le Thi Thu Thao, Tran Tinh Hien, Andrew McMichael, Jeremy Farrar, Sarah Rowland-Jones

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing - over half the world's population now live in areas at risk of infection. Most infections are asymptomatic, but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Severe forms of dengue are epidemiologically associated with repeated infection by more than one of the four dengue virus serotypes. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T-cells may also influence disease phenotype. Methods and Findings: Virus-specific cytotoxic T lymphocytes (CTL) showing high level cross reactivity between dengue serotypes could be expanded from blood samples taken during the acute phase of secondary dengue infection. These could not be detected in convalescence when only CTL populations demonstrating significant serotype specificity were identified. Dengue cross-reactive CTL clones derived from these patients were of higher avidity than serotype-specific clones and produced much higher levels of both type 1 and certain type 2 cytokines, many previously implicated in dengue pathogenesis. Conclusion: Dengue serotype cross-reactive CTL clones showing high avidity for antigen produce higher levels of inflammatory cytokines than serotype-specific clones. That such cells cannot be expanded from convalescent samples suggests that they maybe depleted, perhaps as a consequence of activation-induced cell death. Such high avidity cross-reactive memory CTL may produce inflammatory cytokines during the course of secondary infection, contributing to the pathogenesis of vascular leak. These cells appear to be subsequently deleted leaving a more serotype-specific memory CTL pool. Further studies are needed to relate these cellular observations to disease phenotype in a large group of patients. If confirmed they have significant implications for understanding the role of virus-specific CTL in pathogenesis of dengue disease.

Original languageEnglish
Article numbere1192
JournalPLoS ONE
Volume2
Issue number12
DOIs
Publication statusPublished - 5 Dec 2007

Cite this

Dong, Tao ; Moran, Edward ; Vinh Chau, Nguyen Van ; Simmons, Cameron ; Luhn, Kerstin ; Peng, Yanchun ; Wills, Bridget ; Phuong Dung, Nguyen ; Thi Thu Thao, Le ; Hien, Tran Tinh ; McMichael, Andrew ; Farrar, Jeremy ; Rowland-Jones, Sarah. / High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection. In: PLoS ONE. 2007 ; Vol. 2, No. 12.
@article{37539c5ec2e446d7b0bdc4b21fdc307e,
title = "High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection",
abstract = "Background: Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing - over half the world's population now live in areas at risk of infection. Most infections are asymptomatic, but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Severe forms of dengue are epidemiologically associated with repeated infection by more than one of the four dengue virus serotypes. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T-cells may also influence disease phenotype. Methods and Findings: Virus-specific cytotoxic T lymphocytes (CTL) showing high level cross reactivity between dengue serotypes could be expanded from blood samples taken during the acute phase of secondary dengue infection. These could not be detected in convalescence when only CTL populations demonstrating significant serotype specificity were identified. Dengue cross-reactive CTL clones derived from these patients were of higher avidity than serotype-specific clones and produced much higher levels of both type 1 and certain type 2 cytokines, many previously implicated in dengue pathogenesis. Conclusion: Dengue serotype cross-reactive CTL clones showing high avidity for antigen produce higher levels of inflammatory cytokines than serotype-specific clones. That such cells cannot be expanded from convalescent samples suggests that they maybe depleted, perhaps as a consequence of activation-induced cell death. Such high avidity cross-reactive memory CTL may produce inflammatory cytokines during the course of secondary infection, contributing to the pathogenesis of vascular leak. These cells appear to be subsequently deleted leaving a more serotype-specific memory CTL pool. Further studies are needed to relate these cellular observations to disease phenotype in a large group of patients. If confirmed they have significant implications for understanding the role of virus-specific CTL in pathogenesis of dengue disease.",
author = "Tao Dong and Edward Moran and {Vinh Chau}, {Nguyen Van} and Cameron Simmons and Kerstin Luhn and Yanchun Peng and Bridget Wills and {Phuong Dung}, Nguyen and {Thi Thu Thao}, Le and Hien, {Tran Tinh} and Andrew McMichael and Jeremy Farrar and Sarah Rowland-Jones",
year = "2007",
month = "12",
day = "5",
doi = "10.1371/journal.pone.0001192",
language = "English",
volume = "2",
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Dong, T, Moran, E, Vinh Chau, NV, Simmons, C, Luhn, K, Peng, Y, Wills, B, Phuong Dung, N, Thi Thu Thao, L, Hien, TT, McMichael, A, Farrar, J & Rowland-Jones, S 2007, 'High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection', PLoS ONE, vol. 2, no. 12, e1192. https://doi.org/10.1371/journal.pone.0001192

High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection. / Dong, Tao; Moran, Edward; Vinh Chau, Nguyen Van; Simmons, Cameron; Luhn, Kerstin; Peng, Yanchun; Wills, Bridget; Phuong Dung, Nguyen; Thi Thu Thao, Le; Hien, Tran Tinh; McMichael, Andrew; Farrar, Jeremy; Rowland-Jones, Sarah.

In: PLoS ONE, Vol. 2, No. 12, e1192, 05.12.2007.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection

AU - Dong, Tao

AU - Moran, Edward

AU - Vinh Chau, Nguyen Van

AU - Simmons, Cameron

AU - Luhn, Kerstin

AU - Peng, Yanchun

AU - Wills, Bridget

AU - Phuong Dung, Nguyen

AU - Thi Thu Thao, Le

AU - Hien, Tran Tinh

AU - McMichael, Andrew

AU - Farrar, Jeremy

AU - Rowland-Jones, Sarah

PY - 2007/12/5

Y1 - 2007/12/5

N2 - Background: Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing - over half the world's population now live in areas at risk of infection. Most infections are asymptomatic, but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Severe forms of dengue are epidemiologically associated with repeated infection by more than one of the four dengue virus serotypes. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T-cells may also influence disease phenotype. Methods and Findings: Virus-specific cytotoxic T lymphocytes (CTL) showing high level cross reactivity between dengue serotypes could be expanded from blood samples taken during the acute phase of secondary dengue infection. These could not be detected in convalescence when only CTL populations demonstrating significant serotype specificity were identified. Dengue cross-reactive CTL clones derived from these patients were of higher avidity than serotype-specific clones and produced much higher levels of both type 1 and certain type 2 cytokines, many previously implicated in dengue pathogenesis. Conclusion: Dengue serotype cross-reactive CTL clones showing high avidity for antigen produce higher levels of inflammatory cytokines than serotype-specific clones. That such cells cannot be expanded from convalescent samples suggests that they maybe depleted, perhaps as a consequence of activation-induced cell death. Such high avidity cross-reactive memory CTL may produce inflammatory cytokines during the course of secondary infection, contributing to the pathogenesis of vascular leak. These cells appear to be subsequently deleted leaving a more serotype-specific memory CTL pool. Further studies are needed to relate these cellular observations to disease phenotype in a large group of patients. If confirmed they have significant implications for understanding the role of virus-specific CTL in pathogenesis of dengue disease.

AB - Background: Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing - over half the world's population now live in areas at risk of infection. Most infections are asymptomatic, but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Severe forms of dengue are epidemiologically associated with repeated infection by more than one of the four dengue virus serotypes. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T-cells may also influence disease phenotype. Methods and Findings: Virus-specific cytotoxic T lymphocytes (CTL) showing high level cross reactivity between dengue serotypes could be expanded from blood samples taken during the acute phase of secondary dengue infection. These could not be detected in convalescence when only CTL populations demonstrating significant serotype specificity were identified. Dengue cross-reactive CTL clones derived from these patients were of higher avidity than serotype-specific clones and produced much higher levels of both type 1 and certain type 2 cytokines, many previously implicated in dengue pathogenesis. Conclusion: Dengue serotype cross-reactive CTL clones showing high avidity for antigen produce higher levels of inflammatory cytokines than serotype-specific clones. That such cells cannot be expanded from convalescent samples suggests that they maybe depleted, perhaps as a consequence of activation-induced cell death. Such high avidity cross-reactive memory CTL may produce inflammatory cytokines during the course of secondary infection, contributing to the pathogenesis of vascular leak. These cells appear to be subsequently deleted leaving a more serotype-specific memory CTL pool. Further studies are needed to relate these cellular observations to disease phenotype in a large group of patients. If confirmed they have significant implications for understanding the role of virus-specific CTL in pathogenesis of dengue disease.

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U2 - 10.1371/journal.pone.0001192

DO - 10.1371/journal.pone.0001192

M3 - Article

VL - 2

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

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M1 - e1192

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