Therapeutic administration of a monoclonal anti-Il-1β antibody protects against experimental melioidosis

BACKGROUND:: Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3-inflammasome and its downstream product interleukin-1 beta (IL-1β) have been proposed to play crucial roles in melioidosis. In this study we characterized the role of IL-1β more closely and we assessed its therapeutic potential. METHODS:: mRNA expression of inflammasome components was determined in isolated leukocytes of 32 healthy controls and 34 patients with sepsis caused by B. pseudomallei.Wild-type (WT), NLRP3-deficient (Nlrp3) and Asc mice were infected with B. pseudomallei. In additional experiments, infected WT mice were treated with an anti-IL-1β antibody. After 24, 48 and 72?hours (h) mice were sacrificed and organs were harvested. Furthermore, survival studies were performed. RESULTS:: Patients with melioidosis exhibited lower mRNA levels of caspase-1, NLRP3 and ASC. Bacterial dissemination and organ damage were increased in B. pseudomallei-infected Nlrp3 and Asc mice, together with a reduced pulmonary cell influx. Anti-IL-1β treatment of B. pseudomallei challenged mice resulted in strongly reduced bacterial counts, organ damage and pulmonary granulocyte influx together with reduced mortality. Postponement of anti-IL-1β treatment for 24?h post-infection still protected mice during melioidosis. CONCLUSION:: Expression of caspase-1, NLRP3 and ASC is altered in melioidosis patients. In mice, both NLRP3 and ASC contribute to the host defense against melioidosis. Anti-IL-1β treatment protects mice against B. pseudomallei infection and might be a novel treatment strategy in melioidosis

Therapeutic administration of a monoclonal anti-Il-1β antibody protects against experimental melioidosis

BACKGROUND:: Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3-inflammasome and its downstream product interleukin-1 beta (IL-1β) have been proposed to play crucial roles in melioidosis. In this study we characterized the role of IL-1β more closely and we assessed its therapeutic potential. METHODS:: mRNA expression of inflammasome components was determined in isolated leukocytes of 32 healthy controls and 34 patients with sepsis caused by B. pseudomallei.Wild-type (WT), NLRP3-deficient (Nlrp3) and Asc mice were infected with B. pseudomallei. In additional experiments, infected WT mice were treated with an anti-IL-1β antibody. After 24, 48 and 72?hours (h) mice were sacrificed and organs were harvested. Furthermore, survival studies were performed. RESULTS:: Patients with melioidosis exhibited lower mRNA levels of caspase-1, NLRP3 and ASC. Bacterial dissemination and organ damage were increased in B. pseudomallei-infected Nlrp3 and Asc mice, together with a reduced pulmonary cell influx. Anti-IL-1β treatment of B. pseudomallei challenged mice resulted in strongly reduced bacterial counts, organ damage and pulmonary granulocyte influx together with reduced mortality. Postponement of anti-IL-1β treatment for 24?h post-infection still protected mice during melioidosis. CONCLUSION:: Expression of caspase-1, NLRP3 and ASC is altered in melioidosis patients. In mice, both NLRP3 and ASC contribute to the host defense against melioidosis. Anti-IL-1β treatment protects mice against B. pseudomallei infection and might be a novel treatment strategy in melioidosis

Thrombocytopenia impairs host defense against Burkholderia pseudomallei (Melioidosis)

Background Infection with the gram-negative bacillus Burkholderia pseudomallei (melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection. Methods Association between platelet counts and mortality was determined in 1160 patients with culture-proven melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibα–deficient mice were conducted. Results Thrombocytopenia was present in 31% of patients at admission and predicted mortality in melioidosis patients even after adjustment for confounders. In our murine-melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibα–deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung. Conclusions Thrombocytopenia predicts mortality in melioidosis patients and, during experimental melioidosis, platelets play a protective role in both innate immunity and vascular integrity