How can Naturally Occurring Fatty Acids Neutralize
            <i>Listeria</i>
            ?

Kallipolitis, Birgitte H.

doi:10.2217/fmb-2017-0176

Cited by 4 publications

(6 citation statements)

References 16 publications

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“…Naturally occurring FFAs have also been suggested as potential antivirulence agents against pathogenic bacteria (25,30). Indeed, an earlier study reported a decreased invasiveness of L. monocytogenes into Caco-2 cells upon exposure to FFAs present in milk (41); however, the mechanism behind this effect was not unveiled.…”

Section: Discussionmentioning

confidence: 99%

“…In S. enterica, OA interacts directly with the virulence regulator HilD and affects its DNA binding ability, leading to a downregulation of virulence genes required for the expression of the Salmonella pathogenicity island 1 type III secretion system (8). Notably, ToxT and HilD belong to the AraC family of transcription regulators, whereas PrfA belongs to the CRP/FNR family (25). Altogether, these findings suggest that intestinal pathogens are using specific FFAs as signaling molecules to control the DNA binding activity of key virulence regulators.…”

Section: Discussionmentioning

confidence: 99%

“…Due to its undeniable importance for listerial pathogenesis, PrfA became a desirable target for antivirulence agents, and therefore, recent studies have focused on identifying compounds that could act to prevent PrfA-dependent virulence gene expression (21,25). We have recently shown that distinct FFAs can act as antimicrobial as well as virulence-inhibitory agents in L. monocytogenes (9).…”

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confidence: 99%

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Free Fatty Acids Interfere with the DNA Binding Activity of the Virulence Regulator PrfA of Listeria monocytogenes

et al. 2020

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ABSTRACT Naturally occurring free fatty acids (FFAs) are recognized as potent antimicrobial agents that also affect the production of virulence factors in bacterial pathogens. In the foodborne pathogen Listeria monocytogenes, some medium- and long-chain FFAs act as antimicrobial agents as well as signaling compounds, causing a repression of transcription of virulence genes. We previously observed that the master virulence regulator PrfA is involved in both the antimicrobial and virulence-inhibitory response of L. monocytogenes to selected FFAs, but the underlying mechanisms are presently unknown. Here, we present a systematic analysis of the antimicrobial and PrfA-inhibitory activities of medium- and long-chain FFAs of various carbon chain lengths and degrees of saturation. We observed that exposure to specific antimicrobial and nonantimicrobial FFAs prevented PrfA-dependent activation of virulence gene transcription and reduced the levels of PrfA-regulated virulence factors. Thus, an antimicrobial activity was not compulsory for the PrfA-inhibitory ability of an FFA. In vitro binding experiments revealed that PrfA-inhibitory FFAs were also able to prevent the constitutively active variant PrfA* from binding to the PrfA box in the promoter region of the virulence gene hly, whereas noninhibitory FFAs did not affect its ability to bind DNA. Notably, the unsaturated FFAs inhibited the DNA binding activity of PrfA* most efficiently. Altogether, our findings support a model in which specific FFAs orchestrate a generalized reduction of the virulence potential of L. monocytogenes by directly targeting the key virulence regulator PrfA. IMPORTANCE Listeria monocytogenes is a Gram-positive pathogen able to cause foodborne infections in humans and animals. Key virulence genes in L. monocytogenes are activated by the transcription regulator PrfA, a DNA binding protein belonging to the CRP/FNR family. Various signals from the environment are known to affect the activity of PrfA, either positively or negatively. Recently, we found that specific medium- and long-chain free fatty acids act as antimicrobial agents as well as signaling compounds in L. monocytogenes. Here, we show that both antimicrobial and nonantimicrobial free fatty acids inhibit PrfA-dependent activation of virulence gene transcription by interfering with the DNA binding activity of PrfA. Our findings suggest that free fatty acids could be candidates for alternative therapies against L. monocytogenes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Free Fatty Acids Interfere with the DNA Binding Activity of the Virulence Regulator PrfA of Listeria monocytogenes

et al. 2020

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“…We appreciate that we have not examined alterations to listerial expression of virulence factors that may occur as a result of luminal alterations of nutrients. For instance, altered responses in Listeria have been reported in response to exposure to various fatty acids in vitro [48] and may therefore have the potential to influence infectivity. It is interesting to note that other studies have demonstrated that a high-fat food delivery matrix can increase infectivity of L. monocytogenes in murine [49] or primate [50] models.…”

Section: Discussionmentioning

confidence: 99%

Short-term consumption of a high-fat diet increases host susceptibility to Listeria monocytogenes infection

et al. 2019

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BackgroundA westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice.ResultsWe determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver.ConclusionsWe adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.Electronic supplementary materialThe online version of this article (10.1186/s40168-019-0621-x) contains supplementary material, which is available to authorized users.

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“…Together, these conditions strongly influence the ability of L. monocytogenes to cause disease ( Tiensuu et al, 2019 ). We previously found that specific dietary free fatty acids (FFAs) act as signaling molecules to reduce virulence factor expression in L. monocytogenes by a mechanism that involves direct inhibition of PrfA ( Kallipolitis, 2017 ; Sternkopf Lillebæk et al, 2017 ; Dos Santos et al, 2020 ). Interestingly, exposure to specific FFAs prevented the constitutively active variant PrfA* from binding to the PrfA box in the promoter region of hly , encoding LLO ( Dos Santos et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The Global Regulator CcpA of Listeria monocytogenes Confers Sensitivity to Antimicrobial Fatty Acids

et al. 2022

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Free fatty acids (FFAs) are known to exhibit antimicrobial and anti-virulent properties against bacterial pathogens. Specific FFAs, such as lauric acid (LA; C12:0), exert both effects against the foodborne pathogen Listeria monocytogenes: at low levels, LA acts to inhibit the activity of the virulence regulator PrfA, whereas at higher levels, LA inhibits bacterial growth. Deletion of prfA is known to promote tolerance toward antimicrobial FFAs, suggesting that the response of L. monocytogenes to anti-virulent and antimicrobial FFAs could be linked. In this study, we explored the response of L. monocytogenes toward antimicrobial FFAs holding an anti-virulence activity by isolating strains that can grow at high concentrations of LA. We found that LA-tolerant isolates carry mutations in the gene encoding the global regulator CcpA. Importantly, we discovered that mutation or deletion of ccpA protect L. monocytogenes against the antimicrobial activity of FFAs, whereas the ccpA mutants remain sensitive toward FFA’s PrfA inhibitory effect. A regulatory link involving CcpA, connecting the response toward the antimicrobial and anti-virulence activities of FFAs, is therefore unlikely. To further study how deletion of ccpA promotes FFA tolerance, we performed a transcriptomic analysis of the response to LA. Our data indicated that the FFA-tolerant phenotype of the ∆ccpA strain is not induced upon LA exposure but appears to be an inherent phenotypic trait of the ccpA deletion mutation. Interestingly, we found that the bacterial surface of L. monocytogenes becomes more hydrophilic upon deletion of ccpA, and we demonstrate that CcpA plays a role in the response of L. monocytogenes to other stress conditions, including low pH and antibiotics. Altogether, our study revealed that regulatory activities of CcpA lead to an increased hydrophobicity of the bacterial surface, which may confer sensitivity of L. monocytogenes against the antimicrobial activity of FFAs. Notably, CcpA is not involved in responding to the PrfA inhibitory effect of FFAs, showing that FFA-tolerant strains can still be targeted by the anti-virulent activity of FFAs.

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How can Naturally Occurring Fatty Acids Neutralize Listeria ?

Cited by 4 publications

References 16 publications

Free Fatty Acids Interfere with the DNA Binding Activity of the Virulence Regulator PrfA of Listeria monocytogenes

Free Fatty Acids Interfere with the DNA Binding Activity of the Virulence Regulator PrfA of Listeria monocytogenes

Short-term consumption of a high-fat diet increases host susceptibility to Listeria monocytogenes infection

The Global Regulator CcpA of Listeria monocytogenes Confers Sensitivity to Antimicrobial Fatty Acids

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