title: Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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 postinfection still protected mice during melioidosis.
  
  
  
  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.
authors.affiliation: *Center for Infection and Immunity Amsterdam (CINIMA)/Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands †Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands ‡Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand §Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK ||Novartis Institutes for BioMedical Research, Basel, Switzerland ¶Department of Internal medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Tassili A F
authors.initials: TA
authors.lastname: Weehuizen
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Lankelma
authors.forename: Hanna K
authors.initials: HK
authors.lastname: De Jong
authors.forename: Onno J
authors.initials: OJ
authors.lastname: De Boer
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Alex F
authors.initials: AF
authors.lastname: De Vos
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016957:Burkholderia pseudomallei / Q000472:pathogenicity; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008554:Melioidosis / Q000188:drug therapy* / Q000382:microbiology*; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger