Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Burkholderia pseudomallei, the causative agent of melioidosis, is a gram-negative bacterium capable of causing either acute lethal sepsis or chronic but eventually fatal disease in infected individuals. However, despite the clinical importance of this infection in areas where it is endemic, there is essentially no information on the mechanisms of protective immunity to the bacterium. We describe here a murine model of either acute or chronic infection with B. pseudomallei in Taylor Outbred (TO) mice which mimics many features of the human pathology. Intraperitoneal infection of TO mice at doses of >10(6) CFU resulted in acute septic shock and death within 2 days. In contrast, at lower doses mice were able to clear the inoculum from the liver and spleen over a 3- to 4-week period, but persistence of the organism at other sites resulted in a chronic infection of between 2 and 16 months duration which was eventually lethal in all of the animals tested. Resistance to acute infection with B. pseudomallei was absolutely dependent upon the production of gamma interferon (IFN-gamma) in vivo. Administration of neutralizing monoclonal antibody against IFN-gamma lowered the 50% lethal dose from >5 x 10(5) to ca. 2 CFU and was associated with 8,500- and 4,400-fold increases in the bacterial burdens in the liver and spleen, respectively, together with extensive destruction of lymphoid architecture in the latter organ within 48 h. Neutralization of either tumor necrosis factor alpha or interleukin-12 but not granulocyte-macrophage colony-stimulating factor, also increased susceptibility to infection in vivo. Together, these results provide the first evidence of a host protective mechanism against B. pseudomallei. The rapid production of IFN-gamma within the first day of infection determines whether the infection proceeds to an acute lethal outcome or becomes chronic.
 ...
PMID:Obligatory role of gamma interferon for host survival in a murine model of infection with Burkholderia pseudomallei. 1037 44

Burkholderia pseudomallei, the causative agent of melioidosis, is a gram-negative bacillus endemic to areas of southeast Asia and northern Australia. Presently, there is no licensed vaccine for B. pseudomallei and the organism is refractive to antibiotic therapy. The bacterium is known to survive and multiply inside both phagocytic and nonphagocytic host cells and may be able to spread directly from cell to cell. Current vaccine delivery systems are unlikely to induce the correct immune effectors to stimulate a protective response to the organism. In this study, we have developed a procedure to utilize dendritic cells as a vaccine delivery vector to induce cell-mediated immune responses to B. pseudomallei. Dendritic cells were produced by culturing murine bone marrow progenitor cells in medium containing granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha. Purified dendritic cells were pulsed with heat-killed whole-cell B. pseudomallei and used to immunize syngeneic mice. Strong cellular immune responses were elicited by this immunization method, although antibody responses were low. Booster immunizations of either a second dose of dendritic cells or heat-killed B. pseudomallei were administered to increase the immune response. Immunized animals were challenged with fully virulent B. pseudomallei, and protection was demonstrated in those with strong humoral and cell-mediated immunity. These results indicate the importance of both cell-mediated and humoral immune mechanisms in protection against intracellular pathogens.
 ...
PMID:Humoral and cell-mediated adaptive immune responses are required for protection against Burkholderia pseudomallei challenge and bacterial clearance postinfection. 1611 15