Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
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Tassili A F Weehuizen1, Jacqueline M Lankelma, Hanna K De Jong
1*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.
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 postinfection 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.
Insights
Interleukin-1 beta (IL-1β) plays a key role in melioidosis defense. Blocking IL-1β in mice reduced bacterial load and mortality, suggesting its therapeutic potential for this serious infection.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- Melioidosis, a sepsis cause in Southeast Asia/Australia, is linked to Burkholderia pseudomallei.
- The NLRP3 inflammasome and its product, interleukin-1 beta (IL-1β), are implicated in melioidosis pathogenesis.
Purpose of the Study:
- To investigate the role of IL-1β in melioidosis.
- To evaluate the therapeutic potential of targeting IL-1β.
Main Methods:
- Measured inflammasome component mRNA in melioidosis patients and healthy controls.
- Infected wild-type, NLRP3-deficient, and ASC-deficient mice with B. pseudomallei.
- Administered anti-IL-1β antibody to infected mice and assessed outcomes, including survival.
Main Results:
- Melioidosis patients showed lower caspase-1, NLRP3, and ASC mRNA levels.
- NLRP3 and ASC deficiency in mice increased bacterial dissemination and organ damage.
- Anti-IL-1β treatment reduced bacterial counts, organ damage, and mortality in infected mice, even when delayed.
Conclusions:
- Caspase-1, NLRP3, and ASC expression changes in melioidosis.
- NLRP3 and ASC are crucial for host defense against B. pseudomallei.
- Anti-IL-1β therapy shows promise as a novel treatment for melioidosis.
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