Interleukin 10 inhibits pro-inflammatory cytokine responses and killing of Burkholderia pseudomallei.

Melioidosis, caused by Burkholderia pseudomallei, is endemic in northeastern Thailand and Northern Australia. Severe septicemic melioidosis is associated with high levels of pro-inflammatory cytokines and is correlated with poor clinical outcomes. IL-10 is an immunoregulatory cytokine, which in other infections can control the expression of pro-inflammatory cytokines, but its role in melioidosis has not been addressed. Here, whole blood of healthy seropositive individuals (n = 75), living in N. E. Thailand was co-cultured with B. pseudomallei and production of IL-10 and IFN-γ detected and the cellular sources identified. CD3- CD14+ monocytes were the main source of IL-10. Neutralization of IL-10 increased IFN-γ, IL-6 and TNF-α production and improved bacteria killing. IFN-γ production and microbicidal activity were impaired in individuals with diabetes mellitus (DM). In contrast, IL-10 production was unimpaired in individuals with DM, resulting in an IL-10 dominant cytokine balance. Neutralization of IL-10 restored the IFN-γ response of individuals with DM to similar levels observed in healthy individuals and improved killing of B. pseudomallei in vitro. These results demonstrate that monocyte derived IL-10 acts to inhibit potentially protective cell mediated immune responses against B. pseudomallei, but may also moderate the pathological effects of excessive cytokine production during sepsis

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