title: T Cell Immunity to the Alkyl Hydroperoxide Reductase of Burkholderia pseudomallei: A Correlate of Disease Outcome in Acute Melioidosis.
abstract: There is an urgent need for a better understanding of adaptive immunity to Burkholderia pseudomallei, the causative agent of melioidosis that is frequently associated with sepsis or death in patients in Southeast Asia and Northern Australia. The imperative to identify vaccine targets is driven both by the public health agenda in these regions and biological threat concerns. In several intracellular bacterial pathogens, alkyl hydroperoxidase reductases are upregulated as part of the response to host oxidative stress, and they can stimulate strong adaptive immunity. We show that alkyl hydroperoxidase reductase (AhpC) of B. pseudomallei is strongly immunogenic for T cells of 'humanized' HLA transgenic mice and seropositive human donors. Some T cell epitopes, such as p6, are able to bind diverse HLA class II heterodimers and stimulate strong T cell immunity in mice and humans. Importantly, patients with acute melioidosis who survive infection show stronger T cell responses to AhpC relative to those who do not. Although the sequence of AhpC is virtually invariant among global B. pseudomallei clinical isolates, a Cambodian isolate varies only in C-terminal truncation of the p6 T cell epitope, raising the possibility of selection by host immunity. This variant peptide is virtually unable to stimulate T cell immunity. For an infection in which there has been debate about centrality of T cell immunity in defense, these observations support a role for T cell immunity to AhpC in disease protection.
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors: Catherine
authors: C
authors: Reynolds
authors: CEA, Institut de Biologie et de Technologies de Saclay, Labex Laboratoire de Recherche sur le Médicament et l'Innovation Thérapeutique and Institut de Recherche Vaccinale, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif sur Yvette, France;
authors: Amélie
authors: A
authors: Goudet
authors: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors: Kemajittra
authors: K
authors: Jenjaroen
authors: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors: Manutsanun
authors: M
authors: Sumonwiriya
authors: Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40000, Thailand;
authors: Darawan
authors: D
authors: Rinchai
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
authors: Julie
authors: J
authors: Musson
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors: Saskia
authors: S
authors: Overbeek
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors: Julia
authors: J
authors: Makinde
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors: Kathryn
authors: K
authors: Quigley
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors: Jiten
authors: J
authors: Manji
authors: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom;
authors: Natasha
authors: N
authors: Spink
authors: Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia;
authors: Pagnarith
authors: P
authors: Yos
authors: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors: Vanaporn
authors: V
authors: Wuthiekanun
authors: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom;
authors: Gregory
authors: G
authors: Bancroft
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
authors: John
authors: J
authors: Robinson
authors: Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40000, Thailand;
authors: Ganjana
authors: G
authors: Lertmemongkolchai
authors: Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; and.
authors: Susanna
authors: S
authors: Dunachie
authors: CEA, Institut de Biologie et de Technologies de Saclay, Labex Laboratoire de Recherche sur le Médicament et l'Innovation Thérapeutique and Institut de Recherche Vaccinale, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif sur Yvette, France;
authors: Bernard
authors: B
authors: Maillere
authors: School of Medicine, University of St Andrews, St Andrews KY16 9TF, United Kingdom.
authors: Matthew
authors: M
authors: Holden
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors: Daniel
authors: D
authors: Altmann
authors: Lung Immunology Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom; r.boyton@imperial.ac.uk.
authors: Rosemary
authors: R
authors: Boyton
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D016957:Burkholderia pseudomallei / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005838:Genotype; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D008554:Melioidosis / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D054464:Peroxiredoxins / Q000235:genetics* / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D054464:Peroxiredoxins