Shigella-induced emergency granulopoiesis protects zebrafish larvae from secondary infection

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Title: Shigella-induced emergency granulopoiesis protects zebrafish larvae from secondary infection
Authors: Willis, A
Lo Celso, C
Filloux, A
Torraca, V
Mazon Moya, M
Castro Gomes, M
Shelley, J
Mostowy, S
Item Type: Journal Article
Publication Date: 2018-06-26
2018-07-02T11:33:46Z
Abstract: Emergency granulopoiesis is a hematopoietic program of stem cell-driven neutrophil production used to counteract immune cell exhaustion following infection. Shigella flexneri is a Gram-negative enteroinvasive pathogen controlled by neutrophils. In this study, we use a Shigella-zebrafish (Danio rerio) infection model to investigate emergency granulopoiesis in vivo. We show that stem cell-driven neutrophil production occurs in response to Shigella infection and requires macrophage-independent signaling by granulocyte colony-stimulating factor (Gcsf). To test whether emergency granulopoiesis can function beyond homoeostasis to enhance innate immunity, we developed a reinfection assay using zebrafish larvae that have not yet developed an adaptive immune system. Strikingly, larvae primed with a sublethal dose of Shigella are protected against a secondary lethal dose of Shigella in a type III secretion system (T3SS)-dependent manner. Collectively, these results highlight a new role for emergency granulopoiesis in boosting host defense and demonstrate that zebrafish larvae can be a valuable in vivo model to investigate innate immune memory. IMPORTANCE Shigella is an important human pathogen of the gut. Emergency granulopoiesis is the enhanced production of neutrophils by hematopoietic stem and progenitor cells (HSPCs) upon infection and is widely considered a homoeostatic mechanism for replacing exhausted leukocytes. In this study, we developed a Shigella-zebrafish infection model to investigate stem cell-driven emergency granulopoiesis. We discovered that zebrafish initiate granulopoiesis in response to Shigella infection, via macrophage-independent signaling of granulocyte colony-stimulating factor (Gcsf). Strikingly, larvae primed with a sublethal dose of Shigella are protected against a secondary lethal dose of Shigella in a type III secretion system (T3SS)-dependent manner. Taken together, we show that zebrafish infection can be used to capture Shigella-mediated stem cell-driven granulopoiesis and provide a new model system to study stem cell biology in vivo. Our results also highlight the potential of manipulating stem cell-driven granulopoiesis to boost innate immunity and combat infectious disease.
Issue Date: 26-Jun-2018
Date of Acceptance: 30-May-2018
URI: http://hdl.handle.net/10044/1/60466
DOI: https://dx.doi.org/10.1128/mBio.00933-18
ISSN: 2150-7511
Publisher: American Society for Microbiology
Journal / Book Title: mBio
Volume: 9
Issue: 3
Copyright Statement: © 2018 Willis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Lister Institute of Preventive Medicine
Commission of the European Communities
Funder's Grant Number: 097411/Z/11/ZR
MR/J006874/1B
n/a
700088
Keywords: Shigella
emergency granulopoiesis
neutrophils
stem cells
zebrafish
0605 Microbiology
Publication Status: Published
Article Number: e00933-18
Appears in Collections:Department of Medicine
Faculty of Medicine
Faculty of Natural Sciences



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