About: The Salmonella LysR family regulator, RipR, activates the SPI-13 encoded itaconate degradation cluster

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About: The Salmonella LysR family regulator, RipR, activates the SPI-13 encoded itaconate degradation cluster Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	The Salmonella LysR family regulator, RipR, activates the SPI-13 encoded itaconate degradation cluster
Creator	Hersch, Steven Navarre, William
source	BioRxiv
abstract	Itaconate is a dicarboxylic acid that inhibits the isocitrate lyase enzyme of the bacterial glyoxylate shunt. Activated macrophages have been shown to produce itaconate, suggesting that these immune cells may employ this metabolite as a weapon against invading bacteria. Here we demonstrate that, in vitro, itaconate can exhibit bactericidal effects under acidic conditions similar to the pH of a macrophage phagosome. In parallel, successful pathogens including Salmonella have acquired a genetic operon encoding itaconate degradation proteins, which are induced heavily in macrophages. We characterize the regulation of this operon by the neighbouring gene, ripR, in specific response to itaconate. Moreover, we develop an itaconate biosensor based on the operon promoter that can detect itaconate in a semi-quantitative manner and, when combined with the ripR gene, is sufficient for itaconate-regulated expression in E. coli. Using this biosensor with fluorescence microscopy, we observe bacteria responding to itaconate in the phagosomes of macrophage and provide additional evidence that interferon-γ stimulates macrophage itaconate synthesis and that J774 mouse macrophages produce substantially more itaconate than the human THP-1 monocyte cell line. In summary, we examine the role of itaconate as an antibacterial metabolite in mouse and human macrophage, characterize the regulation of Salmonella’s defense against it, and develop it as a convenient itaconate biosensor and inducible promoter system. Importance In response to invading bacteria, immune cells can produce a molecule called itaconate, which can inhibit microbial metabolism. Here we show that itaconate can also directly kill Salmonella when combined with moderate acidity, further supporting itaconate’s role as an antibacterial weapon. We also discover how Salmonella recognizes itaconate and activates a defense to degrade it, and we harness this response to make a biosensor that detects the presence of itaconate. This biosensor is versatile, working in Salmonella enterica or lab strains of Escherichia coli, and can detect itaconate quantitatively in the environment and in immune cells. By understanding how immune cells kill bacteria and how the microbes defend themselves, we can better develop novel antibiotics to inhibit pathogens such as Salmonella.
has issue date	2020-05-05(xsd:dateTime)
bibo:doi	10.1101/648865
has license	biorxiv
sha1sum (hex)	c610a552ae7decf624e17189aeb6e5049890f8e2
schema:url	https://doi.org/10.1101/648865
resource representing a document's title	The Salmonella LysR family regulator, RipR, activates the SPI-13 encoded itaconate degradation cluster
schema:publication	bioRxiv
resource representing a document's body	covid:c610a552ae7decf624e17189aeb6e5049890f8e2#body_text
is schema:about of	named entity 'bactericidal' named entity 'Salmonella enterica' named entity 'versatile' named entity 'survive' named entity 'macrophages' named entity 'induced' named entity 'operon' named entity 'pathogens' named entity 'intestine' named entity 'response' named entity 'virulence' named entity 'Salmonella' named entity 'antibacterial' named entity 'bacteria' named entity 'gene' named entity 'genetic' named entity 'support' named entity 'fluorescence microscopy' named entity 'isocitrate lyase' named entity 'recognizes' named entity 'serovar' named entity 'inhibit' named entity 'antibiotics' named entity 'encoding' named entity 'gut' named entity 'pathogens' named entity 'operon' named entity 'referred' named entity 'host organism' named entity 'regulation' named entity 'bacterial' named entity 'cluster' named entity 'bacteria' named entity 'bacteria' named entity 'microbes' named entity 'serovar' named entity 'macrophage' named entity 'macrophage' named entity 'itaconate' named entity 'Salmonella' named entity 'ripR' named entity 'gene' named entity 'macrophages' named entity 'E. coli' named entity 'bacteria' named entity 'Salmonella' named entity 'biosensor' named entity 'operon' named entity 'phagosome' named entity 'resident microbiota' named entity 'pathogens' named entity 'itaconate' named entity 'macrophage' named entity 'Salmonella' named entity 'macrophage' named entity 'organic acid' named entity 'bactericidal' named entity 'Pseudomonas' named entity 'carboxyl groups' named entity 'gene product' named entity 'macrophage' named entity 'enzyme' named entity 'metabolites' named entity 'RipR' named entity 'itaconate' named entity 'ccl' named entity 'Salmonella enterica' named entity 'Salmonella' named entity 'itaconate' named entity 'succinate' named entity 'ATP' named entity 'THP-1' named entity 'Salmonella' named entity 'macrophage' named entity 'macrophage' named entity 'IFN-γ' named entity 'itaconate' named entity 'Paratyphi' named entity 'macrophage' named entity 'stimulant' named entity 'Salmonella enterica' named entity 'metabolite' named entity 'Salmonella'

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