title: Prophylactic application of CpG oligonucleotides augments the early host response and confers protection in acute melioidosis.
abstract: Prophylactic administration of CpG oligodeoxynucleotides (CpG ODNs) is known to confer protection against lethal sepsis caused by Burkholderia pseudomallei in the mouse model. The mechanisms whereby CpG regulates the innate immune response to provide protection against B. pseudomallei, however, are poorly characterized. In the present study, we demonstrate that intranasal treatment of mice with Class C CpG, results in recruitment of inflammatory monocytes and neutrophils to the lung at 48 h post-treatment. Mice infected with B. pseudomallei 48 h post-CpG treatment had reduced organ bacterial load and significantly altered cytokine and chemokine profiles concomitant with protection as compared to control animals. CpG administration reduced the robust production of chemokines and pro-inflammatory cytokines in blood, lung and spleen, observed following infection of non-treated animals. Death of control animals coincided with the time of peak cytokine production (day 1-3), while a moderate; sustained cytokine production in CpG-treated animals was associated with survival. In general, CpG treatment resulted in diminished expression of cytokines and chemokines post-infection, though IL-12p40 was released in larger quantities in CpG treated animals. In contrast to CpG-treated animals, the lungs of infected control animals were infiltrated with leukocytes, especially neutrophils, and large numbers of necrotic lesions were observed in lung sections. Therapeutic treatment of B. pseudomallei-infected animals with CpG at 24 h post-infection did not impact survival compared to control animals. In summary, protection of CpG-treated animals was associated with recruitment of inflammatory monocytes and neutrophils into the lungs prior to infection. These responses correspond with early control of bacterial growth, a dampened inflammatory cytokine/chemokine response, reduced lung pathology, and greatly increased survival. In contrast, a delay in recruitment of inflammatory cell populations, despite a robust production of pro-inflammatory cytokines, was associated with poorly controlled bacterial growth, severe lung pathology, and death of control animals.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Judy
authors.forename: Katherine
authors.initials: K
authors.lastname: Taylor
authors.forename: Arpaporn
authors.initials: A
authors.lastname: Deeraksa
authors.forename: R Katie
authors.initials: RK
authors.lastname: Johnston
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Endsley
authors.forename: Sudhamathi
authors.initials: S
authors.lastname: Vijayakumar
authors.forename: Judith F
authors.initials: JF
authors.lastname: Aronson
authors.forename: D Mark
authors.initials: DM
authors.lastname: Estes
authors.forename: Alfredo G
authors.initials: AG
authors.lastname: Torres
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D016957:Burkholderia pseudomallei / Q000302:isolation & purification / Q000472:pathogenicity*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008554:Melioidosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015996:Survival Rate
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D018925:Chemokines; D016207:Cytokines; D009838:Oligodeoxyribonucleotides