Caspase-6 mediates resistance against Burkholderia pseudomallei infection and influences the expression of detrimental cytokines

Alexander Bartel,Katrin Breitbach,Verena Hopf,André Göhler,R Mark Wooten

doi:10.1371/journal.pone.0180203

Abstract

Caspase-6 is a member of the executioner caspases and known to play a role in innate and adaptive immune processes. However, its role in infectious diseases has rarely been addressed yet. We here examined the impact of caspase-6 in an in vivo infection model using the Gram-negative rod Burkholderia pseudomallei, causing the infectious disease melioidosis that is endemic in tropical and subtropical areas around the world. Caspase-6-/- and C57BL/6 wild type mice were challenged with B. pseudomallei for comparing mortality, bacterial burden and inflammatory cytokine expression. Bone-marrow derived macrophages were used to analyse the bactericidal activity in absence of caspase-6. Caspase-6 deficiency was associated with higher mortality and bacterial burden in vivo after B. pseudomallei infection. The bactericidal activity of caspase-6-/- macrophages was impaired compared to wild type cells. Caspase-6-/- mice showed higher expression of the IL-1β gene, known to be detrimental in murine melioidosis. Expression of the IL-10 gene was also increased in caspase-6-/- mice as early as 6 hours after infection. Treatment with exogenous IL-10 rendered mice more susceptible against B. pseudomallei challenge. Thus, caspase-6 seems to play a crucial role for determining resistance against the causative agent of melioidosis. To our knowledge this is the first report showing that caspase-6 is crucial for mediating resistance in an in vivo infection model. Caspase-6 influences the expression of detrimental cytokines and therefore seems to be important for achieving a well-balanced immune response that contributes for an efficient elimination of the pathogen.

Highlights

Caspases are a family of cysteine proteases that are involved in the induction of various forms of cell death and play a role in inflammatory processes [1,2]
Since the in vivo data led us speculate that caspase-6 confers resistance in an early stage after B. pseudomallei challenge, we investigated whether caspase-6 might have an impact on the bactericidal activity of B. pseudomallei infected macrophages
Caspase6-/- macrophages were generally able to reduce the number of intracellular bacteria, the number of the remaining bacteria was still approx. 3-fold higher compared to wild type macrophages 24 hours after infection (Fig 2)

Summary

Introduction

Caspases are a family of cysteine proteases that are involved in the induction of various forms of cell death and play a role in inflammatory processes [1,2]. A previous report could show that caspase-6 cleaves the receptor-interacting protein kinase-1 and it was suggested that caspase-6 might be important for controlling inflammatory events in dying cells [6]. It was reported that caspase-6 plays a role for neutrophil-driven activation of macrophages due to the cleavage of IL-1 receptor associated kinase M [7]. The authors of this study demonstrated that caspase-6-/- mice were protected to some degree during cecal lesion induced peritonitis and sepsis [7]. To our knowledge, this is the only report that has been addressing the role for caspase-6 in an in vivo infection model yet

Methods

Results

Conclusion