Macrophages target Salmonella by Lc3-associated phagocytosis in a systemic infection model

Masud, Samrah, Prajsnar, Tomasz K., Torraca, V., Lamers, Gerda E. M., Benning, Marianne, Van der Vaart, Michiel and Meijer, Annemarie H. 2019. Macrophages target Salmonella by Lc3-associated phagocytosis in a systemic infection model. Autophagy. 15 (5), pp. 796-812. https://doi.org/10.1080/15548627.2019.1569297

TitleMacrophages target Salmonella by Lc3-associated phagocytosis in a systemic infection model
TypeJournal article
AuthorsMasud, Samrah, Prajsnar, Tomasz K., Torraca, V., Lamers, Gerda E. M., Benning, Marianne, Van der Vaart, Michiel and Meijer, Annemarie H.
Abstract

Innate immune defense against intracellular pathogens, like Salmonella, relies heavily on the autophagy machinery of the host. This response is studied intensively in epithelial cells, the target of Salmonella during gastrointestinal infections. However, little is known of the role that autophagy plays in macrophages, the predominant carriers of this pathogen during systemic disease. Here we utilize a zebrafish embryo model to study the interaction of S. enterica serovar Typhimurium with the macroautophagy/autophagy machinery of macrophages in vivo. We show that phagocytosis of live but not heat-killed Salmonella triggers recruitment of the autophagy marker GFP-Lc3 in a variety of patterns labeling tight or spacious bacteria-containing compartments, also revealed by electron microscopy. Neutrophils display similar GFP-Lc3 associations, but genetic modulation of the neutrophil/macrophage balance and ablation experiments show that macrophages are critical for the defense response. Deficiency of atg5 reduces GFP-Lc3 recruitment and impairs host resistance, in contrast to atg13 deficiency, indicating that Lc3-Salmonella association at this stage is independent of the autophagy preinitiation complex and that macrophages target Salmonella by Lc3-associated phagocytosis (LAP). In agreement, GFP-Lc3 recruitment and host resistance are impaired by deficiency of Rubcn/Rubicon, known as a negative regulator of canonical autophagy and an inducer of LAP. We also found strict dependency on NADPH oxidase, another essential factor for LAP. Both Rubcn and NADPH oxidase are required to activate a Salmonella biosensor for reactive oxygen species inside infected macrophages. These results identify LAP as the major host protective autophagy-related pathway responsible for macrophage defense against Salmonella during systemic infection.

JournalAutophagy
Journal citation15 (5), pp. 796-812
ISSN1554-8627
1554-8635
Year2019
PublisherTaylor & Francis
Publisher's version
License
CC BY-NC-ND 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1080/15548627.2019.1569297
Web address (URL)https://publons.com/publon/21758557/
Publication dates
Published2019
Published online24 Jan 2019

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