title: Human T cell responses to Japanese encephalitis virus in health and disease.
abstract: Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus.
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, England, UK Health Protection Research Unit for Emerging and Zoonotic Infections, University of Liverpool, Liverpool L69 7BE, England, UK Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool L7 8XP, England, UK lturtle@liverpool.ac.uk paul.klenerman@medawar.ox.ac.uk vijaya@mcbl.iisc.ernet.in.
authors.forename: Lance
authors.initials: L
authors.lastname: Turtle
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Tanushka
authors.initials: T
authors.lastname: Bali
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, England, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Buxton
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Savita
authors.initials: S
authors.lastname: Chib
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Sajesh
authors.initials: S
authors.lastname: Chan
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soni
authors.affiliation: Department of Microbiology, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, England, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Isenman
authors.affiliation: Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
authors.forename: Prachi
authors.initials: P
authors.lastname: Fadnis
authors.affiliation: Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
authors.forename: Manjunatha M
authors.initials: MM
authors.lastname: Venkataswamy
authors.affiliation: Department of Microbiology, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India Department of Paediatrics, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India.
authors.forename: Vishali
authors.initials: V
authors.lastname: Satishkumar
authors.affiliation: Department of Infection and Travel Medicine, University Hospital of St. James, Leeds Teaching Hospitals, National Health Service Trust, Leeds LS9 7TF, England, UK.
authors.forename: Penny
authors.initials: P
authors.lastname: Lewthwaite
authors.affiliation: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, England, UK.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kurioka
authors.affiliation: Department of Microbiology, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Department of Paediatrics, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India.
authors.forename: M Veera
authors.initials: MV
authors.lastname: Shankar
authors.affiliation: Department of Paediatrics, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India.
authors.forename: Riyaz
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Department of Microbiology, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India Department of Paediatrics, Vijayanagar Institute of Medical Science Medical College, Bellary 583104, India.
authors.forename: Ashia
authors.initials: A
authors.lastname: Begum
authors.affiliation: Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
authors.forename: Vasanthapuram
authors.initials: V
authors.lastname: Ravi
authors.affiliation: Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Desai
authors.affiliation: Center for Vaccine Development, Institute of Molecular Biosciences, Mahidol University at Salaya, Bangkok 73170, Thailand.
authors.forename: Sutee
authors.initials: S
authors.lastname: Yoksan
authors.affiliation: Department of Virology, Armed Forces Research Institute of Medical Science, Bangkok 10400, Thailand.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fernandez
authors.affiliation: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, England, UK.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Willberg
authors.affiliation: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, England, UK.
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kloverpris
authors.affiliation: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, England, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Conlon
authors.affiliation: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, England, UK lturtle@liverpool.ac.uk paul.klenerman@medawar.ox.ac.uk vijaya@mcbl.iisc.ernet.in.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Satchidanandam
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, England, UK Health Protection Research Unit for Emerging and Zoonotic Infections, University of Liverpool, Liverpool L69 7BE, England, UK Walton Center National Health Service Foundation Trust, Liverpool L9 7LJ, England, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D003429:Cross Reactions / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology; D004664:Encephalitis Virus, Japanese / Q000276:immunology*; D004672:Encephalitis, Japanese / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D017361:Viral Nonstructural Proteins / Q000276:immunology*
chemical_list: C573415:IFNG protein, human; C100315:NS1 protein, Flavivirus; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma