Fatty Acids Abolish
            <i>Shigella</i>
            Virulence by Inhibiting Its Master Regulator, VirF

Trirocco, Rita; Pasqua, Martina; Tramonti, Angela; Grossi, Milena; Colonna, Bianca; Paiardini, Alessandro; Prosseda, Gianni

doi:10.1128/spectrum.00778-23

Cited by 3 publications

(14 citation statements)

References 71 publications

(90 reference statements)

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“…In contrast, a recent report found that treatment with palmitoleic acid did not lead to decreased levels of VirF. 37 This discrepancy can be attributed to the fact that in our experiments, after treatment with fatty acid the production of new protein was halted by adding an antibiotic cocktail. This is important because as cells grow, they produce new protein, diluting the effect of the treatment which might lead to such incongruities.…”

Section: Discussioncontrasting

confidence: 89%

“…In comparison, increasing the carbon tail length or changing the orientation of the cis -unsaturation at the second carbon to trans- reduced the binding affinity of the fatty acid. Supporting these data, a recent report by Trirocco et al 37 also showed that binding of VirF to virB promoter DNA was reduced in the presence of medium- and long-chain fatty acids, with long-chain unsaturated fatty acids showing higher effectiveness. The authors predict that VirF has a distinct binding “cleft” which can accommodate saturated fatty acids in an extended conformation using the amino acid H212.…”

Section: Discussionsupporting

confidence: 58%

“…VirF is also an AraC-type protein, 36 and recently it was shown that certain fatty acids, including diffusible signal factors, can reduce the virulence of S. flexneri by binding to VirF. 37 , 38 The authors showed that many long chain fatty acids, including palmitoleic acid, can directly prevent the ability of VirF to initiate virB transcription and subsequent invasion gene expression. However, the physiological relevance of this interaction to the virulence of S. flexneri remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 89%

Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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Shigella flexneri utilizes intestinal signals to control its virulence

Chowdhury,

Bitar,

Bell

et al. 2023

Gut Microbes

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“…VirF is regulated at the transcriptional level by several environmental stimuli, such as temperature, pH, and osmolarity, and at the post-transcriptional level by MiaA 10 . Very recently, we have shown that the activity of VirF is directly controlled also by fatty acids (FAs) 11 . In particular, FAs such as lauric, capric, myristoleic, palmitoleic and sapienic acid bind VirF and inactivate its transcription-promoting activity, probably by causing the protein structure to change from a free, functional (“open”) state to a FA-bound, non-functional (“closed”) form.…”

Section: Introductionmentioning

confidence: 99%

“…Considering the high structural similarity between XcDSF, BDSF, and lauric acid (Fig. S1 ), a previously characterized inhibitor of VirF activity 11 , we asked whether XcDSF and BDSF could inhibit Shigella virulence by preventing the transcription-promoting activity of the VirF protein. In the present study we show, by in silico, in vitro and in vivo experiments, that XcDSF and BDSF directly interact with VirF, leading to a significant decrease in virB transcription, thus hindering the expression of the entire virulence system of Shigella and causing a defective phenotype characterized by insufficient invasion of host cells and by delayed proliferation within them.…”

Section: Introductionmentioning

confidence: 99%

Diffusible signal factors (DSFs) bind and repress VirF, the leading virulence activator of Shigella flexneri

Trirocco

Pasqua

Tramonti

et al. 2023

Sci Rep

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Shigella, the aetiological agent of human bacillary dysentery, controls the expression of its virulence determinants through an environmentally stimulated cascade of transcriptional activators. VirF is the leading activator and is essential for proper virulence expression. In this work, we report on in vitro and in vivo experiments showing that two autoinducers of the DSF family, XcDSF and BDSF interact with the jelly roll module of VirF causing its inhibition and affecting the expression of the entire virulence system of Shigella, including its ability to invade epithelial cells. We propose a molecular model explaining how the binding of XcDSF and BDSF causes inhibition of VirF by preventing its dimerization. Overall, our experimental results suggest that XcDSF and BDSF may contribute to ”colonisation resistance” in the human gut or, alternatively, may be exploited for the fine-tuning of Shigella virulence expression as the bacterium migrates from the lumen to approach the intestinal mucosa. Our findings also stress how a detailed understanding of the interaction of DSF ligands with VirF may contribute to the rational development of innovative antivirulence drugs to treat shigellosis.

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Shigella flexneri remodeling and consumption of host lipids during infection

Ascari,

Frölich,

Zang

et al. 2023

J Bacteriol

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Shigella flexneri is a major cause of bacillary dysentery in the developing world, predominantly affecting the pediatric age group, with malnutrition being a common co-morbidity. Lipids are key nutritional components, and their abundance and composition are likely to influence the pathobiology of S. flexneri. S. flexneri expresses a plethora of polysaccharides on its cell surface, but how this hydrophilic surface layer influences S. flexneri interaction with hydrophobic host molecules, such as fatty acids and lipids, is not well understood. In this study, we sought to interrogate how this hydrophilic layer affects S. flexneri during its intracellular lifestyle and how lipid homeostasis changes in both the host and pathogen. We characterized changes in S. flexneri cell envelope composition and surface-associated glycolipids, in particular lipopolysaccharide (LPS), during different phases of infection. We found that a dynamic capacity in LPS expression is necessary for the pathogen to manage delicate interaction with host fatty acids and maintain optimum virulence. Additionally, through confocal immunofluorescent microscopy, coupled with transcriptional and lipid analyses, we demonstrate that S. flexneri induces major host lipid remodeling during infection, by hijacking host lipid homeostasis pathways to its own benefit. Finally, this study suggests that fatty acid supplementation can influence the persistence and magnitude of S. flexneri infection. This work provides novel insights into the potential roles of balanced and sufficient dietary fatty acid intake in protection against gastroenteric pathogen infection. IMPORTANCE Bacterial pathogens have vastly distinct sites that they inhabit during infection. This requires adaptation due to changes in nutrient availability and antimicrobial stress. The bacterial surface is a primary barrier, and here, we show that the bacterial pathogen Shigella flexneri increases its surface decorations when it transitions to an intracellular lifestyle. We also observed changes in bacterial and host cell fatty acid homeostasis. Specifically, intracellular S. flexneri increased the expression of their fatty acid degradation pathway, while the host cell lipid pool was significantly depleted. Importantly, bacterial proliferation could be inhibited by fatty acid supplementation of host cells, thereby providing novel insights into the possible link between human malnutrition and susceptibility to S. flexneri .

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Fatty Acids Abolish Shigella Virulence by Inhibiting Its Master Regulator, VirF

Abstract: In the absence of a valid vaccine, the main therapeutic approach currently used to treat shigellosis is based on the use of antibiotics. The emergence of antibiotic resistance jeopardizes the future effectiveness of this approach.

Cited by 3 publications

References 71 publications

Shigella flexneri utilizes intestinal signals to control its virulence

Shigella flexneri utilizes intestinal signals to control its virulence

Diffusible signal factors (DSFs) bind and repress VirF, the leading virulence activator of Shigella flexneri

Shigella flexneri remodeling and consumption of host lipids during infection

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