CD4+ T cell epitopes of FliC conserved between strains of Burkholderia: implications for vaccines against melioidosis and cepacia complex in cystic fibrosis.
Burkholderia pseudomallei is the causative agent of melioidosis characterized by pneumonia and fatal septicemia and prevalent in Southeast Asia. Related Burkholderia species are strong risk factors of mortality in cystic fibrosis (CF). The B. pseudomallei flagellar protein FliC is strongly seroreactive and vaccination protects challenged mice. We assessed B. pseudomallei FliC peptide binding affinity to multiple HLA class II alleles and then assessed CD4 T cell immunity in HLA class II transgenic mice and in seropositive individuals in Thailand. T cell hybridomas were generated to investigate cross-reactivity between B. pseudomallei and the related Burkholderia species associated with Cepacia Complex CF. B. pseudomallei FliC contained several peptide sequences with ability to bind multiple HLA class II alleles. Several peptides were shown to encompass strong CD4 T cell epitopes in B. pseudomallei-exposed individuals and in HLA transgenic mice. In particular, the p38 epitope is robustly recognized by CD4 T cells of seropositive donors across diverse HLA haplotypes. T cell hybridomas against an immunogenic B. pseudomallei FliC epitope also cross-reacted with orthologous FliC sequences from Burkholderia multivorans and Burkholderia cenocepacia, important pathogens in CF. Epitopes within FliC were accessible for processing and presentation from live or heat-killed bacteria, demonstrating that flagellin enters the HLA class II Ag presentation pathway during infection of macrophages with B. cenocepacia. Collectively, the data support the possibility of incorporating FliC T cell epitopes into vaccination programs targeting both at-risk individuals in B. pseudomallei endemic regions as well as CF patients.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE2 4HH, United Kingdom;
Julie A
JA
Musson
Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College, London W12 0NN, United Kingdom;
Catherine J
CJ
Reynolds
Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand;
Darawan
D
Rinchai
Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand;
Arnone
A
Nithichanon
Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand;
Prasong
P
Khaenam
Commiseriat à l'Energie Atomique, Insititut de Biologie et de Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), 91191 Gif Sur Yvette, France; and.
Emmanuel
E
Favry
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
Natasha
N
Spink
Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College, London W12 0NN, United Kingdom;
Karen K Y
KK
Chu
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE2 4HH, United Kingdom;
Anthony
A
De Soyza
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
Gregory J
GJ
Bancroft
Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand;
Ganjana
G
Lertmemongkolchai
Commiseriat à l'Energie Atomique, Insititut de Biologie et de Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), 91191 Gif Sur Yvette, France; and.
Bernard
B
Maillere
Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College, London W12 0NN, United Kingdom;
Rosemary J
RJ
Boyton
Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College, London W12 0NN, United Kingdom;
Daniel M
DM
Altmann
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE2 4HH, United Kingdom; john.robinson@ncl.ac.uk.
John H
JH
Robinson
D000483:Alleles; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology; D019117:Burkholderia / Q000276:immunology*; D019121:Burkholderia Infections / Q000235:genetics / Q000276:immunology*; D016957:Burkholderia pseudomallei / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D003550:Cystic Fibrosis / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D008554:Melioidosis / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology
D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D007371:Interferon-gamma