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Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System.
mBio. 2016 Feb 16; 7(1):e02170-15.MBIO

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.

Authors+Show Affiliations

Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA slauch@illinois.edu golubeva@illinois.edu.Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA slauch@illinois.edu golubeva@illinois.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26884427

Citation

Golubeva, Yekaterina A., et al. "Intestinal Long-Chain Fatty Acids Act as a Direct Signal to Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System." MBio, vol. 7, no. 1, 2016, pp. e02170-15.
Golubeva YA, Ellermeier JR, Cott Chubiz JE, et al. Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System. mBio. 2016;7(1):e02170-15.
Golubeva, Y. A., Ellermeier, J. R., Cott Chubiz, J. E., & Slauch, J. M. (2016). Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System. MBio, 7(1), e02170-15. https://doi.org/10.1128/mBio.02170-15
Golubeva YA, et al. Intestinal Long-Chain Fatty Acids Act as a Direct Signal to Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System. mBio. 2016 Feb 16;7(1):e02170-15. PubMed PMID: 26884427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System. AU - Golubeva,Yekaterina A, AU - Ellermeier,Jeremy R, AU - Cott Chubiz,Jessica E, AU - Slauch,James M, Y1 - 2016/02/16/ PY - 2016/2/18/entrez PY - 2016/2/18/pubmed PY - 2016/12/16/medline SP - e02170 EP - 15 JF - mBio JO - mBio VL - 7 IS - 1 N2 - UNLABELLED: 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. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/26884427/Intestinal_Long_Chain_Fatty_Acids_Act_as_a_Direct_Signal_To_Modulate_Expression_of_the_Salmonella_Pathogenicity_Island_1_Type_III_Secretion_System_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=26884427 DB - PRIME DP - Unbound Medicine ER -