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Cited by 8Bacterial Genetics and BiotechnologyStreptococcal Infections and TreatmentsCancer, Lipids, and Metabolism

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The double-edged role of FASII regulator FabT in Streptococcus pyogenes infection

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Lambert, Clara, Gaillard, Marine, Wongdontree, Paprapach, Bachmann, Caroline, Hautcoeur, Antoine, Gloux, Karine, Guilbert, Thomas, Méhats, Celine, Prost, Bastien, Solgadi, Audrey, Abreu, Sonia, Andrieu, Muriel, Poyart, Claire, Gruss, Alexandra, Fouet, Agnes·2024·Nature Communications
DOI 10.1038/s41467-024-52637-3PMC PMC11452403

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Abstract

Abstract In Streptococcus pyogenes , the type II fatty acid (FA) synthesis pathway FASII is feedback- controlled by the FabT repressor bound to an acyl-Acyl carrier protein. Despite FabT defects being linked to reduced virulence in animal models, spontaneous fabT mutants arise in vivo . To resolve this paradox, we characterized the conditions and mechanisms that require FabT activity, and those that promote fabT mutant emergence. The primary fabT mutant defect is energy dissipation: specific nutrients are consumed, but the mutant fails to grow on human tissue, cells, or cell filtrates where nutrients are limited. These features explain the FabT requirement during infection. Conversely, fabT mutants exhibited a marked growth advantage over the wild-type in biotopes rich in saturated FAs. fabT mutants emerge in this context, where continued FASII activity prevented environmental FA incorporation. An ex vivo muscle model demonstrated that wild-type S. pyogenes was inhibited, while fabT mutant growth was stimulated, but conditional to FASII activity. Our findings elucidate the rationale for emerging fabT mutants that improve survival in lipid-rich biotopes, but lead to a genetic impasse for infection.

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Figures

Fig. 1 FA differences in WT and mFabT strains impact lipid content and composition. a, b HPLC-MS profiles represent the main lipid classes in WT and mFabT grown in indicated media to OD600 = 0.5; lipid profiles and quantifications by class. Lipid concentrations correspond to milligrams extracted from OD600 = 100 equivalents. MGDG, monoglucosyldiacylglycerol; DGDG, diglucosyldiacylglycerol; PG, phosphatidylglycerol; CL, cardiolipin (Supplementary Table 3). c, d, e CL species in WT and mFabT, showing putative deoxidized cardiolipin species (deoxy-CL, designated by a ‘d’ preceding acyl chain features; see Supplementary Table 2); a, b, N = 4, c, d, N = 3, where N corresponds to the number of extractions from independent samples used to identify the lipid species. e Represents proportions of CL and putative deoxy CL in WT and mFabT, as presented in (c, d). a, b, e 2-way ANOVA, Bonferroni post-test. a, b, e Data are presented as mean values +/- SEM. a–d NL, normalization level. Significant p-values are shown. WT, white bars; mFabT, green bars. Hatched bars indicate that culture medium contained Tween 80. f Polymyxin B sensitivity. WT and mFabT were precultured to OD600 = 0.5 in THY or THY-Tween and dilutions were spotted on the same respective solid medium supplemented or not with polymyxin B (PB). Plates are representative of 3 independent experiments. Source data for a, b, and e, are provided as a Source Data file.
Fig. 1 FA differences in WT and mFabT strains impact lipid content and composition. a, b HPLC-MS profiles represent the main lipid classes in WT and mFabT grown in indicated media to OD600 = 0.5; lipid profiles and quantifications by class. Lipid concentrations correspond to milligrams extracted from OD600 = 100 equivalents. MGDG, monoglucosyldiacylglycerol; DGDG, diglucosyldiacylglycerol; PG, phosphatidylglycerol; CL, cardiolipin (Supplementary Table 3). c, d, e CL species in WT and mFabT, showing putative deoxidized cardiolipin species (deoxy-CL, designated by a ‘d’ preceding acyl chain features; see Supplementary Table 2); a, b, N = 4, c, d, N = 3, where N corresponds to the number of extractions from independent samples used to identify the lipid species. e Represents proportions of CL and putative deoxy CL in WT and mFabT, as presented in (c, d). a, b, e 2-way ANOVA, Bonferroni post-test. a, b, e Data are presented as mean values +/- SEM. a–d NL, normalization level. Significant p-values are shown. WT, white bars; mFabT, green bars. Hatched bars indicate that culture medium contained Tween 80. f Polymyxin B sensitivity. WT and mFabT were precultured to OD600 = 0.5 in THY or THY-Tween and dilutions were spotted on the same respective solid medium supplemented or not with polymyxin B (PB). Plates are representative of 3 independent experiments. Source data for a, b, and e, are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 2 FabT regulon in the presence of eFAs and genetic organization of the GAS FASII genes. a Schematic representation of the GAS FabT regulon, comprising genes of the FASII locus and fakB4. Gene positions with names below are represented. Red asterisks, putative FabT binding sites3; bent arrows, transcription start sites; solid arrow, transcript defined by RT-PCRs; dotted arrows, transcripts from previously reported start sites19. b–e Volcano plots of differentially expressed genes, compared as indicated. See Supplementary Table 4 for a complete list. Volcano plots were constructed using GraphPad Prism, by plotting the negative base 10 logarithm of the p-value on the y axis, and the log of the fold change (base 2) on the x axis. P-values for comparisons of peak intensities were calculated by two-sided T-test. Statistical significance was validated by the one-sided Wald test. Padj: calculated p-values were adjusted for multiple testing using the false discovery rate controlling procedure (see Methods section). Gene expression was considered modified in a given condition when the absolute value of log2-Foldchange (FC) was greater than or equal to 1, with an adjusted p-value ≤ 0.05. Data points with low p-values (highly significant) appear at the top of the plot. Source data for b, c, d, and e are provided as a Source Data file.
Fig. 2 FabT regulon in the presence of eFAs and genetic organization of the GAS FASII genes. a Schematic representation of the GAS FabT regulon, comprising genes of the FASII locus and fakB4. Gene positions with names below are represented. Red asterisks, putative FabT binding sites3; bent arrows, transcription start sites; solid arrow, transcript defined by RT-PCRs; dotted arrows, transcripts from previously reported start sites19. b–e Volcano plots of differentially expressed genes, compared as indicated. See Supplementary Table 4 for a complete list. Volcano plots were constructed using GraphPad Prism, by plotting the negative base 10 logarithm of the p-value on the y axis, and the log of the fold change (base 2) on the x axis. P-values for comparisons of peak intensities were calculated by two-sided T-test. Statistical significance was validated by the one-sided Wald test. Padj: calculated p-values were adjusted for multiple testing using the false discovery rate controlling procedure (see Methods section). Gene expression was considered modified in a given condition when the absolute value of log2-Foldchange (FC) was greater than or equal to 1, with an adjusted p-value ≤ 0.05. Data points with low p-values (highly significant) appear at the top of the plot. Source data for b, c, d, and e are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 3 The mFabT strain grows poorly on human tissue ex vivo. a Comparison of GAS WT and mFabT cfus after 8 h growth in static conditions in the presence of human decidua tissue. Bacterial multiplication at the tissue surface in flow conditions (live imaging); b left, Visualization of WTeryR-igfp and mFabTeryR-igfp multiplication in 2D. Poor mFabT growth led to nearly identical images at 1 and 4 h, with some differences highlighted by white arrowheads; right, ratios over time of areas covered by the two strains. c left, 3D-surface heat map of bacterial layer thickness at 1 and 4 h. The x, y, and z axes are scaled, color code in µm; right, ratios over time of bacterial layer mean thickness of WTeryR-igfp and mFabTeryR-igfp strains on decidual tissue. Determinations were based on N = 5 for (a), N = 3 for (b, c), where N corresponds to the number of independent biological replicates performed per condition. For b and c, representative results are shown, and data are presented as mean values +/- SEM. Statistical analyses were done for (a), by a two-sided T test; for (b) and (c), by 2-way ANOVA, Bonferroni post-test. Significant p-values are shown. WT, black symbols or lines; mFabT, green symbols or lines. Source data for (a), (b), and (c) are provided as a Source Data file.
Fig. 3 The mFabT strain grows poorly on human tissue ex vivo. a Comparison of GAS WT and mFabT cfus after 8 h growth in static conditions in the presence of human decidua tissue. Bacterial multiplication at the tissue surface in flow conditions (live imaging); b left, Visualization of WTeryR-igfp and mFabTeryR-igfp multiplication in 2D. Poor mFabT growth led to nearly identical images at 1 and 4 h, with some differences highlighted by white arrowheads; right, ratios over time of areas covered by the two strains. c left, 3D-surface heat map of bacterial layer thickness at 1 and 4 h. The x, y, and z axes are scaled, color code in µm; right, ratios over time of bacterial layer mean thickness of WTeryR-igfp and mFabTeryR-igfp strains on decidual tissue. Determinations were based on N = 5 for (a), N = 3 for (b, c), where N corresponds to the number of independent biological replicates performed per condition. For b and c, representative results are shown, and data are presented as mean values +/- SEM. Statistical analyses were done for (a), by a two-sided T test; for (b) and (c), by 2-way ANOVA, Bonferroni post-test. Significant p-values are shown. WT, black symbols or lines; mFabT, green symbols or lines. Source data for (a), (b), and (c) are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 4 The mFabT strain displays adhesion and growth defects in the presence of human cells or in conditioned cell supernatant. a–d Comparison of WT and mFabT strain adhesion and growth capacities in the presence of human cells, or conditioned supernatants. Endometrial cells, undifferentiated keratinocytes, and differentiated keratinocytes, and their respective conditioned supernatants were used as specified. a Adhesion; b, c, growth (cfu.mL−1). d, left, Bacterial growth kinetics in endometrial conditioned supernatants; right, Live/Dead bacteria assessment after 8 h growth in conditioned supernatants. Growth experiments were started with 103 bacteria per ml. Determinations were based on N = 9, 7, 7 for a (left to right), N = 11, 9, 6 for (b) (left to right), N = 8, 7, 9 for (c) (left to right), and N = 3 for (d). In each case N corresponds to the number of independent biological replicates performed per condition. Analyses were done as follows: a, b Wilcoxon test for endometrial samples, two-sided T-test for keratinocytes; c Wilcoxon test for endometrial cells and undifferentiated keratinocytes, two-sided T-test for differentiated keratinocytes; d 2-way ANOVA, Bonferroni post-test. Significant p-values are shown. a–c Outliers were searched using ROUT method (GraphPad), with Q = 1%. All graphs are presented as mean values +/- SEM. WT, white bars; mFabT, green bars. Source data for (a), (b), (c), and (d) are provided as a Source Data file.
Fig. 4 The mFabT strain displays adhesion and growth defects in the presence of human cells or in conditioned cell supernatant. a–d Comparison of WT and mFabT strain adhesion and growth capacities in the presence of human cells, or conditioned supernatants. Endometrial cells, undifferentiated keratinocytes, and differentiated keratinocytes, and their respective conditioned supernatants were used as specified. a Adhesion; b, c, growth (cfu.mL−1). d, left, Bacterial growth kinetics in endometrial conditioned supernatants; right, Live/Dead bacteria assessment after 8 h growth in conditioned supernatants. Growth experiments were started with 103 bacteria per ml. Determinations were based on N = 9, 7, 7 for a (left to right), N = 11, 9, 6 for (b) (left to right), N = 8, 7, 9 for (c) (left to right), and N = 3 for (d). In each case N corresponds to the number of independent biological replicates performed per condition. Analyses were done as follows: a, b Wilcoxon test for endometrial samples, two-sided T-test for keratinocytes; c Wilcoxon test for endometrial cells and undifferentiated keratinocytes, two-sided T-test for differentiated keratinocytes; d 2-way ANOVA, Bonferroni post-test. Significant p-values are shown. a–c Outliers were searched using ROUT method (GraphPad), with Q = 1%. All graphs are presented as mean values +/- SEM. WT, white bars; mFabT, green bars. Source data for (a), (b), (c), and (d) are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 5 The mFabT strain is more energy-consuming than the WT strain. Metabolomic analysis of conditioned supernatants inoculated with WT or mFabT after 8 or 16 h incubation. Carbohydrate and amino acid consumption by the two strains are compared (see Supplementary Fig. 5 for metabolite levels in noninfected samples, and Supplementary Table 5 for further amino acid results). N = 3, 2-way ANOVA, Bonferroni post-test; Significant p-values are shown. Strains and growth times are at right.
Fig. 5 The mFabT strain is more energy-consuming than the WT strain. Metabolomic analysis of conditioned supernatants inoculated with WT or mFabT after 8 or 16 h incubation. Carbohydrate and amino acid consumption by the two strains are compared (see Supplementary Fig. 5 for metabolite levels in noninfected samples, and Supplementary Table 5 for further amino acid results). N = 3, 2-way ANOVA, Bonferroni post-test; Significant p-values are shown. Strains and growth times are at right.CC BY-NC-ND · PubMed Central
Fig. 6 Continued FASII activity in the mFabT mutant leads to lower eFA incorporation. Membrane FA profiles were compared in WT and mFabT strains grown in THY-C17:1 (100 µM), containing or not the FASII-inhibitor platensimycin (1 µg/mL−1). Left, Representative FA profiles; right, quantified proportions of major FAs. Both strains grew in C17:1 regardless of the presence of platensimycin (Supplementary Table 6). N = 3, where N corresponds to the number of independent biological replicates used in analyses. Data are presented as mean values +/- SEM; 2-way ANOVA, Bonferroni post-test was performed. Significant p-values are shown. WT (black lines, white bars) and mFabT (green lines and bars). Source data are provided as a Source Data file.
Fig. 6 Continued FASII activity in the mFabT mutant leads to lower eFA incorporation. Membrane FA profiles were compared in WT and mFabT strains grown in THY-C17:1 (100 µM), containing or not the FASII-inhibitor platensimycin (1 µg/mL−1). Left, Representative FA profiles; right, quantified proportions of major FAs. Both strains grew in C17:1 regardless of the presence of platensimycin (Supplementary Table 6). N = 3, where N corresponds to the number of independent biological replicates used in analyses. Data are presented as mean values +/- SEM; 2-way ANOVA, Bonferroni post-test was performed. Significant p-values are shown. WT (black lines, white bars) and mFabT (green lines and bars). Source data are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 7 The eFA incorporation defect of mFabT confers a selective advantage in saturated eFA environments, and in a simulated muscle biotope. a Growth of WT (left), and mFabT (right) in THY supplemented with 100 μM saturated FAs, C14:0 or C16:0 and BSA 0.025%. b, Left, Incorporation of exogenous C14:0 and C16:0 from cultures described in (a). Right, Percent C14:0 and C16:0 incorporation from growth experiments. In (a) and (b), data are presented as mean values +/- SEM based on 3 biological replicates; b 2-way ANOVA, Bonferroni post-test. Significant p-values are shown. WT (black lines, white bars) and mFabT (green lines and bars). c, d Strains were spread on solid BHI medium. Pellets of organic ground bovine meat (~15% fat), used as muscle source, were placed on the bacterial lawns. Plates were photographed 36 h after incubation at 37 °C. Arrowheads indicate zones of inhibition (white) or growth (black) around muscle sources. c, Upper WTeryR-igfp and mFabTeryR-igfp strains were grown in BHI Ery 5, and plated on the same solid medium. Lower, schematic representation of GAS strain growth inhibition and stimulation by muscle. d mFabTeryR-igfp was grown in BHI Ery 5 medium containing C17:1 as FA source, without or with platensimycin to turn off FASII. Cultures were then plated on respectively the same solid medium. For c and d, N = 4 and N = 2 respectively, corresponding to biologically independent experiments. Source data for (a) and (b) are provided as a Source Data file.
Fig. 7 The eFA incorporation defect of mFabT confers a selective advantage in saturated eFA environments, and in a simulated muscle biotope. a Growth of WT (left), and mFabT (right) in THY supplemented with 100 μM saturated FAs, C14:0 or C16:0 and BSA 0.025%. b, Left, Incorporation of exogenous C14:0 and C16:0 from cultures described in (a). Right, Percent C14:0 and C16:0 incorporation from growth experiments. In (a) and (b), data are presented as mean values +/- SEM based on 3 biological replicates; b 2-way ANOVA, Bonferroni post-test. Significant p-values are shown. WT (black lines, white bars) and mFabT (green lines and bars). c, d Strains were spread on solid BHI medium. Pellets of organic ground bovine meat (~15% fat), used as muscle source, were placed on the bacterial lawns. Plates were photographed 36 h after incubation at 37 °C. Arrowheads indicate zones of inhibition (white) or growth (black) around muscle sources. c, Upper WTeryR-igfp and mFabTeryR-igfp strains were grown in BHI Ery 5, and plated on the same solid medium. Lower, schematic representation of GAS strain growth inhibition and stimulation by muscle. d mFabTeryR-igfp was grown in BHI Ery 5 medium containing C17:1 as FA source, without or with platensimycin to turn off FASII. Cultures were then plated on respectively the same solid medium. For c and d, N = 4 and N = 2 respectively, corresponding to biologically independent experiments. Source data for (a) and (b) are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 8 Model for emergence of fabT mutants that are attenuated for virulence. a Saturated FAs (SFAs) in a lipid environment favor mFabT emergence. Toxic FAs may be present in initial GAS contacts with the host. Counter-selection would lead to emergence of FA-insensitive fabT mutants, conferring a growth advantage. In a proof of concept, we show that fabT mutants are selected in an SFA environment. b Host cell environment during invasion hinders mFabT growth. Compared to the WT, fabT mutant bacteria fail to develop and die more rapidly when exposed to human cells; they are also impaired for adhesion. Longer SFAs and continued FASII activity in fabT mutants provokes a state of futile bacterial metabolism where metabolite uptake is stimulated, but does not lead to improved growth. Thus, fabT mutants in GAS populations may confer a survival advantage at the inoculation site, but do not withstand host cell infection conditions. Mauve and green circles, WT and mFabT cocci; zoom is on phospholipids. Small yellow circles and lines, lipids and eFA hydrolysis products respectively, small red, blue, pink circles, sugars and amino acid residues.
Fig. 8 Model for emergence of fabT mutants that are attenuated for virulence. a Saturated FAs (SFAs) in a lipid environment favor mFabT emergence. Toxic FAs may be present in initial GAS contacts with the host. Counter-selection would lead to emergence of FA-insensitive fabT mutants, conferring a growth advantage. In a proof of concept, we show that fabT mutants are selected in an SFA environment. b Host cell environment during invasion hinders mFabT growth. Compared to the WT, fabT mutant bacteria fail to develop and die more rapidly when exposed to human cells; they are also impaired for adhesion. Longer SFAs and continued FASII activity in fabT mutants provokes a state of futile bacterial metabolism where metabolite uptake is stimulated, but does not lead to improved growth. Thus, fabT mutants in GAS populations may confer a survival advantage at the inoculation site, but do not withstand host cell infection conditions. Mauve and green circles, WT and mFabT cocci; zoom is on phospholipids. Small yellow circles and lines, lipids and eFA hydrolysis products respectively, small red, blue, pink circles, sugars and amino acid residues.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Lambert, C., Gaillard, M., Wongdontree, P., Bachmann, C., Hautcoeur, A., Gloux, K., Guilbert, T., Méhats, C., Prost, B., Solgadi, A., Abreu, S., Andrieu, M., Poyart, C., Gruss, A., & Fouet, A.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • AgroParisTech (FR)
  • Université Paris-Saclay (FR)
Corresponding author
Gruss, Alexandra
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-10-04
Volume
15
Issue
1
Pages
8593-8593
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-52637-3
PMC
PMC11452403
OpenAlex
W4403135616
Cited by
8
References
3
Citations by year
2026: 5 · 2025: 1 · 2024: 1
FWCI
1.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Agence Nationale de la Recherche (ANR-22-AAMR-0007, ANR‐10_INBS‐04, ANR-10, ANR-16-CE15-0013)
  • Fondation pour la Recherche Médicale (DBF20161136769, FDT202106012831)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Infectious Diseases › Streptococcal Infections and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
Streptococcus pyogenes, fatty acid synthesis regulation, acyl-acyl carrier protein, bacterial virulence, saturated fatty acids, energy dissipation, bacterial fitness
MeSH terms
Animals, Bacterial Proteins, Fatty Acids, Female, Humans, Mutation, Repressor Proteins, Streptococcal Infections, Streptococcus pyogenes, Virulence, Gene Expression Regulation, Bacterial, Mice, Fatty Acid Synthase, Type II

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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