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

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-1? 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.

SUBMITTER: Bartel A

PROVIDER: S-EPMC5501493 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Bartel Alexander A Göhler André A Hopf Verena V Breitbach Katrin K

PloS one 20170707 7

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. pseudomalle ...[more]

PMID: 28686630

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Project description:The cytosolic pathogen Burkholderia pseudomallei and causative agent of melioidosis has been shown to regulate IL-1? and IL-18 production through NOD-like receptor NLRP3 and pyroptosis via NLRC4. Downstream signalling pathways of those receptors and other cell death mechanisms induced during B. pseudomallei infection have not been addressed so far in detail. Furthermore, the role of B. pseudomallei factors in inflammasome activation is still ill defined. In the present study we show that caspase-1 processing and pyroptosis is exclusively dependent on NLRC4, but not on NLRP3 in the early phase of macrophage infection, whereas at later time points caspase-1 activation and cell death is NLRC4- independent. In the early phase we identified an activation pathway involving caspases-9, -7 and PARP downstream of NLRC4 and caspase-1. Analyses of caspase-1/11-deficient infected macrophages revealed a strong induction of apoptosis, which is dependent on activation of apoptotic initiator and effector caspases. The early activation pathway of caspase-1 in macrophages was markedly reduced or completely abolished after infection with a B. pseudomallei flagellin FliC or a T3SS3 BsaU mutant. Studies using cells transfected with the wild-type and mutated T3SS3 effector protein BopE indicated also a role of this protein in caspase-1 processing. A T3SS3 inner rod protein BsaK mutant failed to activate caspase-1, revealed higher intracellular counts, reduced cell death and IL-1? secretion during early but not during late macrophage infection compared to the wild-type. Intranasal infection of BALB/c mice with the BsaK mutant displayed a strongly decreased mortality, lower bacterial loads in organs, and reduced levels of IL-1?, myeloperoxidase and neutrophils in bronchoalveolar lavage fluid. In conclusion, our results indicate a major role for a functional T3SS3 in early NLRC4-mediated caspase-1 activation and pyroptosis and a contribution of late caspase-1-dependent and -independent cell death mechanisms in the pathogenesis of B. pseudomallei infection.

Project description:Burkholderia pseudomallei is an opportunistic pathogen that is responsible for the disease melioidosis in humans and animals. The microbe is a tier 1 select agent because it is highly infectious by the aerosol route, it is inherently resistant to multiple antibiotics, and no licensed vaccine currently exists. Naturally acquired infections result from contact with contaminated soil or water sources in regions of endemicity. There have been few reports investigating the molecular mechanism(s) utilized by B. pseudomallei to survive and persist in ecological niches harboring microbial competitors. Here, we report the isolation of Gram-positive bacteria from multiple environmental sources and show that ∼45% of these isolates are inhibited by B. pseudomallei in head-to-head competition assays. Two competition-deficient B. pseudomallei transposon mutants were identified that contained insertion mutations in the hmqA-G operon. This large biosynthetic gene cluster encodes the enzymes that produce a family of secondary metabolites called 4-hydroxy-3-methyl-2-alkylquinolines (HMAQs). Liquid chromatography and mass spectrometry conducted on filter-sterilized culture supernatants revealed five HMAQs and N-oxide derivatives that were produced by the parental strain but were absent in an isogenic hmqD deletion mutant. The results demonstrate that B. pseudomallei inhibits the growth of environmental Gram-positive bacteria in a contact-independent manner via the production of HMAQs by the hmqA-G operon. IMPORTANCE Burkholderia pseudomallei naturally resides in water, soil, and the rhizosphere and its success as an opportunistic pathogen is dependent on the ability to persist in these harsh habitats long enough to come into contact with a susceptible host. In addition to adapting to limiting nutrients and diverse chemical and physical challenges, B. pseudomallei also has to interact with a variety of microbial competitors. Our research shows that one of the ways in which B. pseudomallei competes with Gram-positive environmental bacteria is by exporting a diverse array of closely related antimicrobial secondary metabolites.

Dataset Information

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

Publications

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

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