A model of immunity to Burkholderia pseudomallei: unique responses following immunization and acute lethal infection.
Burkholderia pseudomallei, the etiological agent of melioidosis, causes significant mortality in endemic regions, but little is known regarding the immune mechanisms required for successful protective immunity. To establish a model of immunization that could be used to study this we screened a library of B. pseudomallei strains for immunogenicity in mice. BALB/c mice were immunized with test strains, and 2 weeks later were given a lethal challenge (LC) of virulent B. pseudomallei. Among 49 strains tested, a single strain, CL04, exhibited strong immunoprotective capacity. Interestingly, CL04 had been cultured from a patient with chronic colonization of B. pseudomallei, which is a rare phenomenon. Mice immunized with 0.1 x LD50 (5 x 10(3) CFU) of CL04 had significantly better survival and lower bacterial loads after LC compared to naïve controls. Dose-response analysis demonstrated more robust immunity after higher immunizing doses, and bacterial inactivation by gamma irradiation diminished the protective effect, indicating a requirement for viable organism for immunity. CL04-induced immunity was demonstrated both in B. pseudomallei-susceptible BALB/c and -resistant C57BL/6 mice. We investigated the gene profile of CL04-induced immunity by analyzing responses to immunization using cDNA microarray. Unique responses involving granulocyte macrophage colony stimulating factor (GM-CSF), the proapoptotic regulator Bad and cyclin-dependent kinase (CDK5) were detected in immunized mice, but these responses were absent in naïve-LC mice. Further, responses differed between mouse strains, indicating dependence on host genetic background. This model will be useful in identifying elements of the immune response required for successful adaptive immunity against B. pseudomallei.
Ulett
Glen C
GC
Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA. g.ulette@ug.edu.au
Labrooy
Justin T
JT
Currie
Bart J
BJ
Barnes
Jodie L
JL
Ketheesan
Natkunam
N
D000818:Animals; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000276:immunology; D001769:Blood / Q000382:microbiology; D016957:Burkholderia pseudomallei / Q000254:growth & development / Q000276:immunology*; D015169:Colony Count, Microbial; D003429:Cross Reactions; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000382:microbiology; D008554:Melioidosis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000276:immunology
D001428:Bacterial Vaccines; C494820:Bad protein, mouse; D014613:Vaccines, Attenuated; D051025:bcl-Associated Death Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse