title: CD4+ T-cell immunity to the Burkholderia pseudomallei ABC transporter LolC in melioidosis.
abstract: Burkholderia pseudomallei causes melioidosis, a disease with a wide range of possible outcomes, from seroconversion and dormancy to sepsis and death. This spectrum of host-pathogen interactions poses challenging questions about the heterogeneity in immunity to B. pseudomallei. Models show protection to be dependent on CD4(+) cells and IFN-γ, but little is known about specific target antigens. Having previously implicated the ABC transporter, LolC, in protective immunity, we here use epitope prediction, HLA-binding studies, HLA-transgenic models and studies of T cells from seropositive individuals to characterize HLA-restricted LolC responses. Immunized mice showed long-lasting memory to the protein, whereas predictive algorithms identified epitopes within LolC that subsequently demonstrated strong HLA class II binding. Immunization of HLA-DR transgenics with LolC stimulated T-cell responses to four of these epitopes. Furthermore, the responsiveness of HLA transgenics to LolC revealed a hierarchy supportive of HLA polymorphism-determined differential susceptibility. Seropositive human donors of diverse HLA class II types showed T-cell responses to LolC epitopes, which are conserved among Burkholderia species including Burkholderia cenocepacia, associated with life-threatening cepacia complex in cystic fibrosis patients and Burkholderia mallei, which causes glanders. These findings suggest a role for LolC epitopes in multiepitope vaccine design for melioidosis and related diseases.
authors.affiliation: Human Disease Immunogenetics Group, Department of Infectious Diseases and Immunity, Imperial College, London, UK.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Chu
authors.forename: Patcharaporn
authors.initials: P
authors.lastname: Tippayawat
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Walker
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Harding
authors.forename: Helen S
authors.initials: HS
authors.lastname: Atkins
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bancroft
authors.forename: Ganjana
authors.initials: G
authors.lastname: Lertmemongkolchai
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000818:Animals; D057508:Burkholderia cenocepacia / Q000276:immunology; D042726:Burkholderia mallei / Q000276:immunology; D016957:Burkholderia pseudomallei / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005896:Glanders / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D008297:Male; D008554:Melioidosis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic / Q000276:immunology
chemical_list: D018528:ATP-Binding Cassette Transporters; D006680:HLA Antigens; D006649:Histocompatibility Antigens