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Using BLaER1 as model for L. major infection of human macrophages to investigate the role of pyroptosis in parasite spreading
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  • Ger van Zandbergen,
  • Kerren Volkmar,
  • Moritz Jaedtka,
  • Iris Baars,
  • Bianca Walber,
  • Katrin Bagola,
  • Andreas Mueller ,
  • Holger Heine
Ger van Zandbergen
Paul-Ehrlich-Institut

Corresponding Author:ger.vanzandbergen@pei.de

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Kerren Volkmar
Paul-Ehrlich-Institut
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Moritz Jaedtka
Paul-Ehrlich-Institut
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Iris Baars
Otto-von-Guericke-Universitat Magdeburg Fakultat fur Naturwissenschaften
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Bianca Walber
Paul-Ehrlich-Institut
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Katrin Bagola
Paul-Ehrlich-Institut
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Andreas Mueller
Otto-von-Guericke-Universitat Magdeburg Fakultat fur Naturwissenschaften
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Holger Heine
Forschungszentrum Borstel Leibniz Lungenzentrum
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Abstract

Leishmania is the causative agent of the tropical neglected disease leishmaniasis and infects macrophages as its definitive host cell . In order to sustain and propagate infections, Leishmania parasites have to complete cycles of exit and re-infection. Yet, the mechanism driving the parasite spread to other cells remains unclear. Recent studies reported pro-inflammatory monocytes as replicative niche of L. major and showed prolonged expression of IL-1β at the site of infection, indicating an activation of the NLRP3 inflammasome and pointing towards pyroptosis as a possible mechanism of parasite spread. To address the species-specific inflammasome activation of human cells we characterized the BLaER1 macrophages as a model for L. major infection. We found that Leishmania can infect, activate and develop in BLaER1 macrophages similar as they can do in primary human macrophages. Harnessing the possibilities of this infection model, we first showed that BLaER1 GSDMD-/- cells, which carry a deletion of the pore-forming protein gasdermin D, are more resistant to pyroptotic cell death and, concomitantly, display a strongly delayed release of intracellular parasite. Using that knockout in a co-incubation assay in comparison with wild type BLaER1 cells, we demonstrate that impairment of the pyroptosis pathway leads to lower rates of parasite spread to new host cells, thus, implicating pyroptotic cell death as a possible exit mechanism of L. major in pro-inflammatory microenvironments.
15 Mar 2023Submitted to Molecular Microbiology
15 Mar 2023Submission Checks Completed
15 Mar 2023Assigned to Editor
20 Mar 2023Reviewer(s) Assigned
14 May 2023Review(s) Completed, Editorial Evaluation Pending
15 May 2023Editorial Decision: Revise Minor
27 Jun 20231st Revision Received
05 Jul 2023Submission Checks Completed
05 Jul 2023Assigned to Editor
06 Jul 2023Reviewer(s) Assigned
02 Aug 2023Review(s) Completed, Editorial Evaluation Pending
03 Aug 2023Editorial Decision: Accept