GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18.

Autor:	Wagner AS; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA., Smith FM; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA., Bennin DA; Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA., Votava JA; Morgridge Institute for Research, Madison, WI, USA., Datta R; Morgridge Institute for Research, Madison, WI, USA., Giese MA; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA., Zhao W; Morgridge Institute for Research, Madison, WI, USA., Skala MC; Morgridge Institute for Research, Madison, WI, USA., Fan J; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.; Morgridge Institute for Research, Madison, WI, USA., Keller NP; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.; Department of Plant Pathology, University of Wisconsin-Madison, WI, USA., Huttenlocher A; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.; Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 11. Date of Electronic Publication: 2024 Oct 11.
DOI:	10.1101/2024.10.11.617742
Abstrakt:	Neutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limited in vitro analysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity against Aspergillus fumigatus . GATA1 knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and more readily execute neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal β-glucan, including an upregulation of the pentose phosphate pathway (PPP), similar to primary human neutrophils in vitro . Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to kill A. fumigatus but is not necessary for the upregulation of PPP. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response. Competing Interests: Competing Interests The authors declare that no competing interests exist.
Databáze:	MEDLINE
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