Salmonella Invasion Is Controlled by Competition among Intestinal Chemical Signals

Chowdhury, Rimi; Bitar, Paulina D. Pavinski; Chapman, Hanora M; Altier, Craig

doi:10.1128/mbio.00012-23

Cited by 6 publications

(7 citation statements)

References 39 publications

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“…In addition, many other intestinal factors than the bile content participate in the complex regulatory network of S . Typhimurium intestinal cell invasion, such as intestinal fatty acid and many other small molecules found in the intestine, and interplay with the intestinal microbiota as well (Lou et al, 2019 ; Rogers et al, 2021 ; Chodhury et al, 2021a , b , 2023 ). Thus, further studies are needed to clarify the possible role of other bile molecules and their possible interaction in the invasion process of S .…”

Section: Discussionmentioning

confidence: 99%

Major primary bile salts repress Salmonella enterica serovar Typhimurium invasiveness partly via the efflux regulatory locus ramRA

Giraud,

Baucheron,

Foubert

et al. 2024

Front. Microbiol.

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Bile represses Salmonella enterica serovar Typhimurium (S. Typhimurium) intestinal cell invasion, but it remains unclear which bile components and mechanisms are implicated. Previous studies reported that bile inhibits the RamR binding to the ramA promoter, resulting in ramA increased transcription, and that ramA overexpression is associated to decreased expression of type III secretion system 1 (TTSS-1) invasion genes and to impaired intestinal cell invasiveness in S. Typhimurium. In this study, we assessed the possible involvement of the ramRA multidrug efflux regulatory locus and individual bile salts in the bile-mediated repression of S. Typhimurium invasion, using Caco-2 intestinal epithelial cells and S. Typhimurium strain ATCC 14028s. Our results indicate that (i) major primary bile salts, chenodeoxycholate and its conjugated-derivative salts, cholate, and deoxycholate, activate ramA transcription in a RamR-dependent manner, and (ii) it results in repression of hilA, encoding the master activator of TTSS-1 genes, and as a consequence in the repression of cellular invasiveness. On the other hand, crude ox bile extract and cholate were also shown to repress the transcription of hilA independently of RamR, and to inhibit cell invasion independently of ramRA. Altogether, these data suggest that bile-mediated repression of S. Typhimurium invasion occurs through pleiotropic effects involving partly ramRA, as well as other unknown regulatory pathways. Bile components other than the bile salts used in this study might also participate in this phenomenon.

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Section: Discussionmentioning

confidence: 99%

Major primary bile salts repress Salmonella enterica serovar Typhimurium invasiveness partly via the efflux regulatory locus ramRA

Giraud,

Baucheron,

Foubert

et al. 2024

Front. Microbiol.

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“…Protein expression was performed as described previously. 24 , 29 , 30 The open reading frame of virF was cloned into pET15b using primers virFpet15 FP/RP and pET15 FP/RP listed in Table 2 , by Gibson assembly. Clones were confirmed by PCR using primers pET15bchk FP/RP and DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…The colonic fatty acids are utilized by many enteric pathogens, such as Salmonella , 24 , 29 , 30 Vibrio 31 and enterotoxigenic E. coli , 32 to regulate their virulence programs. Interestingly, all these pathogens induce their virulence programs by the activation of an AraC-type master regulator, such as HilD, HilC and RtsA of Salmonella , ToxT of Vibrio , and Rns of enterotoxigenic E. coli .…”

Section: Introductionmentioning

confidence: 99%

Shigella flexneri utilizes intestinal signals to control its virulence

Chowdhury,

Bitar,

Bell

et al. 2023

Gut Microbes

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The enteric pathogens have evolved to utilize elements from their surroundings to optimize their infection strategies. A common mechanism to achieve this is to employ intestinal compounds as signals to control the activity of a master regulator of virulence. Shigella flexneri ( S. flexneri ) is a highly infectious entero-invasive pathogen which requires very few organisms to cause invasion of the colonic mucosa. The invasion program is controlled by the virulence master regulator VirF. Here, we show that the fatty acids commonly found in the colon can be exploited by S. flexneri to repress its virulence, allowing it to energetically finance its proliferation, thus increasing its pathogenicity. Colonic fatty acids such as oleic, palmitoleic and cis- 2-hexadecenoic acid were shown to directly bind to VirF and mediate its prompt degradation. These fatty acids also disrupted the ability of VirF to bind to its target DNA, suppressing the transcription of the downstream virulence genes and significantly reducing the invasion of S. flexneri to colonic epithelial cells. Treatment with colonic fatty acids significantly increased the growth rate of the pathogen only under invasion-inducing conditions, showing that the reduction in the burden of virulence promotes a growth advantage. These results demonstrate the process by which S. flexneri can employ intestinal compounds as signals to increase its numbers at its preferred site of invasion, highlighting the mechanism by which the full spectrum of shigellosis is achieved despite a miniscule infectious dose. This highlights an elegant model of environmental adaption by S. flexneri to maximize the pathogenic benefit.

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“…It has also been shown that imported and unmetabolized formic acid functions as a cytoplasmic signal that binds to HilD, the master transcriptional regulator of Salmonella invasion, and prevents the repressive fatty acids from binding to the same. Thus, it enhances the lifetime of HilD and subsequent derepression of invasion genes (18). Also, formate utilization by the respiratory formate dehydrogenase-N (FdnGHI) and formate dehydrogenase-O (FdoGHI) are instrumental in the gut colonization by Salmonella .…”

Section: Introductionmentioning

confidence: 99%

A Tale of Twins: The Distinct Roles of Intracellular and Extracellular Formate in Regulating Flagellar and Pathogenicity Island-1 Genes inSalmonellaTyphimurium

Mukherjee,

Chakravortty

2024

Preprint

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Salmonella enterica is a Gram-negative foodborne pathogen belonging to the family Enterobacteriaceae that accounts for global disease burden and has become a top priority pathogen. The stealthy pathogen Salmonella can sense diverse cues from the host and modify the expression of its virulence factors. Formate is one of the important constituents of Short Chain Fatty Acids (SCFAs) present in the distal ileum and has previously been studied as an important signal to promote invasion in Salmonella Typhimurium. To unravel whether endogenous formate level is also crucial for conferring virulence in Salmonella, we have created genomic knockouts of pflB (Pyruvate-formate lyase) and focA (Formate transporter), the two major contributors to formate pool in Salmonella. Perturbing the intracellular pool of formate by deletion of pflB resulted in some major reprogramming like the loss of flagella and enhanced expression of pathogenicity island-1 genes. Moreover, STM ΔpflB was associated with a higher intracellular pH and membrane damage compared to the WT strain. Our data shows that the membrane damage seen in STM ΔpflB leads to the downregulation of the flagellar apparatus mediated by the extra cytoplasmic sigma factor RpoE. Moreover, this same regulon leads to the enhanced expression of pathogenicity island-1 genes, hilA and prgH. In this study, we show for the first time that endogenous formate levels are of utmost importance to maintain the optimum pH and regulate gene expression in STM. PflB might act as a switch to maintain the optimum cytosolic pH and maximize the virulence of STM under different niches.

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Salmonella Invasion Is Controlled by Competition among Intestinal Chemical Signals

Abstract: Enteric pathogens acutely sense their environment for signals to regulate their virulence functions. We demonstrate here that the enteric pathogen Salmonella utilizes the competition among certain regional intestinal constituents to modulate its virulence determinants in that region.

Cited by 6 publications

References 39 publications

Major primary bile salts repress Salmonella enterica serovar Typhimurium invasiveness partly via the efflux regulatory locus ramRA

Major primary bile salts repress Salmonella enterica serovar Typhimurium invasiveness partly via the efflux regulatory locus ramRA

Shigella flexneri utilizes intestinal signals to control its virulence

A Tale of Twins: The Distinct Roles of Intracellular and Extracellular Formate in Regulating Flagellar and Pathogenicity Island-1 Genes inSalmonellaTyphimurium

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