Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lichtenegger, S; Stiehler, J; Saiger, S; Zauner, A; Kleinhappl, B; Bernecker, C; Schlenke, P; Wagner, GE; Krause, K; Gastager, M; Steinmetz, I.
Burkholderia pseudomallei triggers canonical inflammasome activation in a human primary macrophage-based infection model.
PLoS Negl Trop Dis. 2020; 14(11):e0008840-e0008840
Doi: 10.1371/journal.pntd.0008840
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- Führende Autor*innen der Med Uni Graz
- Steinmetz Ivo
- Wagner-Lichtenegger Sabine
- Co-Autor*innen der Med Uni Graz
- Bernecker Claudia
- Gastager-Ehgartner Magdalena
- Kleinhappl Barbara
- Saiger Sabine
- Schlenke Peter
- Stiehler Julia
- Wagner-Lichtenegger Gabriel
- Zauner Andrea
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- Abstract:
- Most of the current knowledge on Burkholderia pseudomallei-induced inflammasome activation and cell death in macrophages is derived from murine systems. Little is known about the involved bacterial structures and mechanisms in primary human macrophages. This is of particular relevance since murine and human macrophages as well as primary cells and cell lines differ in many aspects of inflammasome activation, including the proteins involved in the recognition of bacterial patterns. In this study, we therefore aimed (i) to establish an in vitro B. pseudomallei infection model with human monocyte-derived primary macrophages from single donors as these cells more closely resemble macrophages in the human host and (ii) to analyze B. pseudomallei-triggered cell death and bacterial elimination in those cells. Our results show that B. pseudomallei-infected primary human macrophages not only release the inflammasome-independent pro-inflammatory cytokines IL-8 and TNF-α, but are also engaged in canonical inflammasome activation as evidenced by caspase-1 and gasdermin D processing. Absence of the B. pseudomallei T3SS-3 needle protein BsaL, a potent activator of the canonical inflammasome, abolished lytic cell death, reduced IL-1β release, and caspase-1 and gasdermin D processing. IFN-γ, known to promote non-canonical inflammasome activation, did not influence pyroptosis induction or IL-1β release from infected primary human macrophages. Nevertheless, it reduced intracellular B. pseudomallei loads, an effect which was partially antagonist by the inhibition of NADPH oxidase. Overall, our data implicate T3SS-3 dependent inflammasome activation and IFN-γ induced immune mechanisms as critical defense mechanisms of human macrophages against B. pseudomallei. In addition, our infection model provides a versatile tool to study human host-pathogen interactions and has the potential to elucidate the role of human individual genetic variations in B. pseudomallei infections.
- Find related publications in this database (using NLM MeSH Indexing)
- Burkholderia pseudomallei - immunology
- Caspase 1 - metabolism
- Cell Line -
- Host-Pathogen Interactions - immunology
- Humans -
- Inflammasomes - immunology
- Interferon-gamma - immunology
- Interleukin-1beta - metabolism
- Interleukin-8 - blood
- Intracellular Signaling Peptides and Proteins - metabolism
- Macrophages - immunology
- Macrophages - microbiology
- Melioidosis - immunology
- Melioidosis - pathology
- NADPH Oxidases - antagonists & inhibitors
- Phosphate-Binding Proteins - metabolism
- Pyroptosis - immunology
- Tumor Necrosis Factor-alpha - blood
- Type III Secretion Systems - metabolism