Gene Regulation by the LiaSR Two-Component System in Streptococcus mutans

Shankar, Manoharan; Mohapatra, Saswat S.; Biswas, Saswati; Biswas, Indranil

doi:10.1371/journal.pone.0128083

Cited by 29 publications

(38 citation statements)

References 43 publications

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“…1 and 3). These data support the critical role of the LiaR-mediated membrane stress responses seen in other bacterial species (24,27). However, supplementation with specific sources of exogenous fatty acids can increase survival of the ⌬liaR strain when challenged with 20% bile or daptomycin (Fig.…”

Section: Discussionsupporting

confidence: 79%

“…One such example is the LiaFSR (lipid II-interacting antibiotic response regulator and sensor) system, which was first identified in Bacillus subtilis (24). In this system, LiaS is a membrane-bound sensor histidine kinase, LiaR is the response regulator, and LiaF (25) is a membrane-anchored negative regulator thought to affect the function of LiaS (25)(26)(27). LiaR was shown to regulate the expression of the liaIHGFSR locus, which, using an unknown mechanism, aids in the cellular response against cell envelope-targeting antibiotics and antimicrobial peptides (25).…”

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confidence: 99%

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Exogenous Fatty Acids Protect Enterococcus faecalis from Daptomycin-Induced Membrane Stress Independently of the Response Regulator LiaR

Harp

Saito

Bourdon

et al. 2016

Appl Environ Microbiol

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Enterococcus faecalis is a commensal bacterium of the gastrointestinal tract that can cause nosocomial infections in immunocompromised humans. The hallmarks of this organism are its ability to survive in a variety of stressful habitats and, in particular, its ability to withstand membrane damage. One strategy used by E. faecalis to protect itself from membrane-damaging agents, including the antibiotic daptomycin, involves incorporation of exogenous fatty acids from bile or serum into the cell membrane. Additionally, the response regulator LiaR (a member of the LiaFSR [lipid II-interacting antibiotic response regulator and sensor] system associated with cell envelope stress responses) is required for the basal level of resistance E. faecalis has to daptomycin-induced membrane damage. This study aimed to determine if membrane fatty acid changes could provide protection against membrane stressors in a LiaR-deficient strain of E. faecalis. We noted that despite the loss of LiaR, the organism readily incorporated exogenous fatty acids into its membrane, and indeed growth in the presence of exogenous fatty acids increased the survival of LiaR-deficient cells when challenged with a variety of membrane stressors, including daptomycin. Combined, our results suggest that E. faecalis can utilize both LiaR-dependent and -independent mechanisms to protect itself from membrane damage. IMPORTANCEEnterococcus faecalis is responsible for a significant number of nosocomial infections. Worse, many of the antibiotics used to treat E. faecalis infection are no longer effective, as this organism has developed resistance to them. The drug daptomycin has been successfully used to treat some of these resistant strains; however, daptomycin-resistant isolates have been identified in hospitals. Many daptomycin-resistant isolates are found to harbor mutations in the genetic locus liaFSR, which is involved in membrane stress responses. Another mechanism shown to increase tolerance to daptomycin involves the incorporation of exogenous fatty acids from host fluids like serum or bile. This improved tolerance was found to be independent of liaFSR and suggests that there are additional ways to impact sensitivity to daptomycin. Thus, further studies are needed to understand how host fatty acid sources can influence antibiotic susceptibility. Enterococcus faecalis is a Gram-positive, facultative anaerobe that resides in the gastrointestinal tract of humans and many other mammalian species (1). Additionally, the organism is known to persist in the external environment for significant periods of time, demonstrating its ability to withstand a variety of changing conditions. Despite the commensal nature of E. faecalis, it is a significant contributor to nosocomial infections, including bloodstream, skin and soft tissue, and urinary tract infections, endocarditis, and meningitis in immunocompromised patients (2, 3). Eradication of E. faecalis, especially in regard to such infections, is challenging as the organism is inherently resistant to a va...

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Exogenous Fatty Acids Protect Enterococcus faecalis from Daptomycin-Induced Membrane Stress Independently of the Response Regulator LiaR

Harp

Saito

Bourdon

et al. 2016

Appl Environ Microbiol

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“…To provide further evidence of LiaFSR activation, we also assayed the transcript levels of spxA2 (spyM3_1799) following the addition of bacitracin. This gene was assayed because deletion of LiaR in S. agalactiae was found to eliminate spxA transcription (30), and more recently, LiaR has been shown to bind to a 25-bp consensus motif in the promoter of the homologous spxA in Streptococcus mutans (34). Examination of the spxA2 promoter sequence in a serotype M3 GAS strain revealed a similar motif with approximately 85% identity (data not shown).…”

Section: Resultsmentioning

confidence: 96%

Increased Pilus Production Conferred by a Naturally Occurring Mutation Alters Host-Pathogen Interaction in Favor of Carriage in Streptococcus pyogenes

et al. 2017

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Studies of the human pathogen group A Streptococcus (GAS) define the carrier phenotype to be an increased ability to adhere to and persist on epithelial surfaces and a decreased ability to cause disease. We tested the hypothesis that a single amino acid change (Arg135Gly) in a highly conserved sensor kinase (LiaS) of a poorly defined GAS regulatory system contributes to a carrier phenotype through increased pilus production. When introduced into an emm serotype-matched invasive strain, the carrier allele (the gene encoding the LiaS protein with an arginine-toglycine change at position 135 [liaS R135G ]) recapitulated a carrier phenotype defined by an increased ability to adhere to mucosal surfaces and a decreased ability to cause disease. Gene transcript analyses revealed that the liaS mutation significantly altered transcription of the genes encoding pilus in the presence of bacitracin. Elimination of pilus production in the isogenic carrier mutant decreased its ability to colonize the mouse nasopharynx and to adhere to and be internalized by cultured human epithelial cells and restored the virulence phenotype in a mouse model of necrotizing fasciitis. We also observed significantly reduced survival of the isogenic carrier mutant compared to that of the parental invasive strain after exposure to human neutrophils. Elimination of pilus in the isogenic carrier mutant increased the level of survival after exposure to human neutrophils to that for the parental invasive strain. Together, our data demonstrate that the carrier mutation (liaS R135G ) affects pilus expression. Our data suggest new mechanisms of pilus gene regulation in GAS and that the invasiveness associated with pilus gene regulation in GAS differs from the enhanced invasiveness associated with increased pilus production in other bacterial pathogens.

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“…In S. mutans, LiaFSR has been shown to regulate 174 genes, some of which specify surface proteins involved in biofilm formation, cell envelope biogenesis proteins, or cell envelope chaperones/proteases (442,447). A 25-bp conserved motif essential for LiaR binding is present upstream of the genes directly controlled by the LiaFSR system (448). Disruption of this system in S. mutans led to augmented sensitivity to antibiotics interfering with lipid II cycling (442).…”

Section: Mechanosensitive Channelsmentioning

confidence: 99%

Stress Physiology of Lactic Acid Bacteria

Papadimitriou

Alegría

Bron

et al. 2016

Microbiol Mol Biol Rev

517

404

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SUMMARYLactic acid bacteria (LAB) are important starter, commensal, or pathogenic microorganisms. The stress physiology of LAB has been studied in depth for over 2 decades, fueled mostly by the technological implications of LAB robustness in the food industry. Survival of probiotic LAB in the host and the potential relatedness of LAB virulence to their stress resilience have intensified interest in the field. Thus, a wealth of information concerning stress responses exists today for strains as diverse as starter (e.g.,Lactococcus lactis), probiotic (e.g., severalLactobacillusspp.), and pathogenic (e.g.,EnterococcusandStreptococcusspp.) LAB. Here we present the state of the art for LAB stress behavior. We describe the multitude of stresses that LAB are confronted with, and we present the experimental context used to study the stress responses of LAB, focusing on adaptation, habituation, and cross-protection as well as on self-induced multistress resistance in stationary phase, biofilms, and dormancy. We also consider stress responses at the population and single-cell levels. Subsequently, we concentrate on the stress defense mechanisms that have been reported to date, grouping them according to their direct participation in preserving cell energy, defending macromolecules, and protecting the cell envelope. Stress-induced responses of probiotic LAB and commensal/pathogenic LAB are highlighted separately due to the complexity of the peculiar multistress conditions to which these bacteria are subjected in their hosts. Induction of prophages under environmental stresses is then discussed. Finally, we present systems-based strategies to characterize the “stressome” of LAB and to engineer new food-related and probiotic LAB with improved stress tolerance.

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Gene Regulation by the LiaSR Two-Component System in Streptococcus mutans

Cited by 29 publications

References 43 publications

Exogenous Fatty Acids Protect Enterococcus faecalis from Daptomycin-Induced Membrane Stress Independently of the Response Regulator LiaR

Exogenous Fatty Acids Protect Enterococcus faecalis from Daptomycin-Induced Membrane Stress Independently of the Response Regulator LiaR

Increased Pilus Production Conferred by a Naturally Occurring Mutation Alters Host-Pathogen Interaction in Favor of Carriage in Streptococcus pyogenes

Stress Physiology of Lactic Acid Bacteria

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