title: Critical role of type 1 cytokines in controlling initial infection with Burkholderia mallei.
abstract: Burkholderia mallei is a gram-negative bacterium which causes the potentially fatal disease glanders in humans; however, there is little information concerning cell-mediated immunity to this pathogen. The role of gamma interferon (IFN-gamma) during B. mallei infection was investigated using a disease model in which infected BALB/c mice normally die between 40 and 60 days postinfection. IFN-gamma knockout mice infected with B. mallei died within 2 to 3 days after infection, and there was uncontrolled bacterial replication in several organs, demonstrating the essential role of IFN-gamma in the innate immune response to this pathogen. Increased levels of IFN-gamma, interleukin-6 (IL-6), and monocyte chemoattractant protein 1 were detected in the sera of immunocompetent mice in response to infection, and splenic mRNA expression of IFN-gamma, IL-6, IL-12p35, and IL-27 was elevated 24 h postinfection. The effects of IL-18, IL-27, and IL-12 on stimulation of the rapid IFN-gamma production were investigated in vitro by analyzing IFN-gamma production in the presence of heat-killed B. mallei. IL-12 was essential for IFN-gamma production in vitro; IL-18 was also involved in induction of IFN-gamma, but IL-27 was not required for IFN-gamma production in response to heat-killed B. mallei. The main cellular sources of IFN-gamma were identified in vitro as NK cells, CD8+ T cells, and TCRgammadelta T cells. Our data show that B. mallei is susceptible to cell-mediated immune responses which promote expression of type 1 cytokines. This suggests that development of effective vaccines against glanders should target the production of IFN-gamma.
authors.affiliation: Biomedical Sciences, Dstl, Porton Down, Salisbury, SP4 0JQ, United Kingdom. carowland@dstl.gov.uk
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Rowland
authors.forename: Ganjana
authors.initials: G
authors.lastname: Lertmemongkolchai
authors.forename: Alison
authors.initials: A
authors.lastname: Bancroft
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.forename: M Stephen
authors.initials: MS
authors.lastname: Lever
authors.forename: Kate F
authors.initials: KF
authors.lastname: Griffin
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Jackson
authors.forename: Michelle
authors.initials: M
authors.lastname: Nelson
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.forename: Richard
authors.initials: R
authors.lastname: Grencis
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bancroft
authors.forename: Roman A
authors.initials: RA
authors.lastname: Lukaszewski
mesh_terms: D000818:Animals; D042726:Burkholderia mallei / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005896:Glanders / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D007378:Interleukins; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma