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Burkholderia pseudomallei triggers canonical inflammasome activation in a human primary macrophage-based infection model.
Lichtenegger, Sabine; Stiehler, Julia; Saiger, Sabine; Zauner, Andrea; Kleinhappl, Barbara; Bernecker, Claudia; Schlenke, Peter; Wagner, Gabriel E; Krause, Kathrin; Gastager, Magdalena; Steinmetz, Ivo.
Afiliação
  • Lichtenegger S; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Stiehler J; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Saiger S; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Zauner A; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Kleinhappl B; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Bernecker C; Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria.
  • Schlenke P; Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria.
  • Wagner GE; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Krause K; Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald, Greifswald, Germany, Current address: Max Planck Unit for the Science of Pathogens, Berlin, Germany.
  • Gastager M; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
  • Steinmetz I; Diagnostic & Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.
PLoS Negl Trop Dis ; 14(11): e0008840, 2020 11.
Article em En | MEDLINE | ID: mdl-33137811
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-1ß release, and caspase-1 and gasdermin D processing. IFN-γ, known to promote non-canonical inflammasome activation, did not influence pyroptosis induction or IL-1ß 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Burkholderia pseudomallei / Inflamassomos / Piroptose / Macrófagos / Melioidose Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Burkholderia pseudomallei / Inflamassomos / Piroptose / Macrófagos / Melioidose Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article