Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System

ABSTRACT Salmonella enterica serovar Typhimurium uses the Salmonella pathogenicity island 1 (SPI1) type III secretion system (T3SS) to induce inflammatory diarrhea and bacterial uptake into intestinal epithelial cells. The expression of hilA, encoding the transcriptional activator of the T3SS struct...

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Autores principales:	Yekaterina A. Golubeva, Jeremy R. Ellermeier, Jessica E. Cott Chubiz, James M. Slauch
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cb9b6810cbfc4b3b954069fe3c63c1e6
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spelling	oai:doaj.org-article:cb9b6810cbfc4b3b954069fe3c63c1e62021-11-15T15:49:40ZIntestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System10.1128/mBio.02170-152150-7511https://doaj.org/article/cb9b6810cbfc4b3b954069fe3c63c1e62016-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02170-15https://doaj.org/toc/2150-7511ABSTRACT Salmonella enterica serovar Typhimurium uses the Salmonella pathogenicity island 1 (SPI1) type III secretion system (T3SS) to induce inflammatory diarrhea and bacterial uptake into intestinal epithelial cells. The expression of hilA, encoding the transcriptional activator of the T3SS structural genes, is directly controlled by three AraC-like regulators, HilD, HilC, and RtsA, each of which can activate hilD, hilC, rtsA, and hilA genes, forming a complex feed-forward regulatory loop. Expression of the SPI1 genes is tightly controlled by numerous regulatory inputs to ensure proper timing in production of the T3SS apparatus. Loss of FadD, an acyl coenzyme A (acyl-CoA) synthetase required for degradation of long-chain fatty acids (LCFAs), was known to decrease hilA expression. We show that free external LCFAs repress expression of hilA independently of FadD and the LCFA degradation pathway. Genetic and biochemical evidence suggests that LCFAs act directly to block primarily HilD activity. Further analyses show that in the absence of FadD, hilA expression is downregulated due to endogenous production of free LCFAs, which are excreted into the culture medium via TolC and then transported back into the bacterial cell via FadL. A fadL mutant is more virulent than the wild-type strain in mouse oral competition assays independently of LCFA degradation, showing that, in the host, dietary LCFAs serve as a signal for proper regulation of SPI1 expression, rather than an energy source. IMPORTANCE To cause disease, Salmonella must respond to diverse environmental cues to express its invasion machinery at the appropriate location in the host intestine. We show that host intestinal free long-chain fatty acids (LCFAs) affect Salmonella invasion by reducing expression of the SPI1 type III secretion system, acting primarily via the AraC-like activator HilD. Degradation of LCFAs is not required for this regulation, showing that free LCFAs serve as a cue to proper intestinal localization to invade host epithelial cells and not as a nutrient source.Yekaterina A. GolubevaJeremy R. EllermeierJessica E. Cott ChubizJames M. SlauchAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 1 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Yekaterina A. Golubeva Jeremy R. Ellermeier Jessica E. Cott Chubiz James M. Slauch Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System
description	ABSTRACT Salmonella enterica serovar Typhimurium uses the Salmonella pathogenicity island 1 (SPI1) type III secretion system (T3SS) to induce inflammatory diarrhea and bacterial uptake into intestinal epithelial cells. The expression of hilA, encoding the transcriptional activator of the T3SS structural genes, is directly controlled by three AraC-like regulators, HilD, HilC, and RtsA, each of which can activate hilD, hilC, rtsA, and hilA genes, forming a complex feed-forward regulatory loop. Expression of the SPI1 genes is tightly controlled by numerous regulatory inputs to ensure proper timing in production of the T3SS apparatus. Loss of FadD, an acyl coenzyme A (acyl-CoA) synthetase required for degradation of long-chain fatty acids (LCFAs), was known to decrease hilA expression. We show that free external LCFAs repress expression of hilA independently of FadD and the LCFA degradation pathway. Genetic and biochemical evidence suggests that LCFAs act directly to block primarily HilD activity. Further analyses show that in the absence of FadD, hilA expression is downregulated due to endogenous production of free LCFAs, which are excreted into the culture medium via TolC and then transported back into the bacterial cell via FadL. A fadL mutant is more virulent than the wild-type strain in mouse oral competition assays independently of LCFA degradation, showing that, in the host, dietary LCFAs serve as a signal for proper regulation of SPI1 expression, rather than an energy source. IMPORTANCE To cause disease, Salmonella must respond to diverse environmental cues to express its invasion machinery at the appropriate location in the host intestine. We show that host intestinal free long-chain fatty acids (LCFAs) affect Salmonella invasion by reducing expression of the SPI1 type III secretion system, acting primarily via the AraC-like activator HilD. Degradation of LCFAs is not required for this regulation, showing that free LCFAs serve as a cue to proper intestinal localization to invade host epithelial cells and not as a nutrient source.
format	article
author	Yekaterina A. Golubeva Jeremy R. Ellermeier Jessica E. Cott Chubiz James M. Slauch
author_facet	Yekaterina A. Golubeva Jeremy R. Ellermeier Jessica E. Cott Chubiz James M. Slauch
author_sort	Yekaterina A. Golubeva
title	Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System
title_short	Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System
title_full	Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System
title_fullStr	Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System
title_full_unstemmed	Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System
title_sort	intestinal long-chain fatty acids act as a direct signal to modulate expression of the <italic toggle="yes">salmonella</italic> pathogenicity island 1 type iii secretion system
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/cb9b6810cbfc4b3b954069fe3c63c1e6
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Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the <italic toggle="yes">Salmonella</italic> Pathogenicity Island 1 Type III Secretion System

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