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A Fluorescence-based Method to Study Bacterial Gene Regulation in Infected Tissues
Published on: February 19, 2019
The double-edged role of FASII regulator FabT in Streptococcus pyogenes infection
Clara Lambert1,2, Marine Gaillard1, Paprapach Wongdontree3
1Université Paris Cité, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France.
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. Although FabT defects confer reduced virulence in animal models, spontaneous fabT mutants arise in vivo. We resolved this paradox by characterizing the conditions and mechanisms requiring FabT activity, and those promoting fabT mutant emergence. The fabT defect leads to energy dissipation, limiting mutant growth on human tissue products, which explains the FabT requirement during infection. Conversely, emerging fabT mutants show superior growth in biotopes rich in saturated FAs, where continued FASII activity limits their incorporation. We propose that membrane alterations and continued FASII synthesis are the primary causes for increased fabT mutant mortality in nutrient-limited biotopes, by failing to stop metabolic consumption. Our findings elucidate the rationale for emerging fabT mutants that improve bacterial survival in lipid-rich biotopes, but lead to a genetic impasse for infection.
Insights
Streptococcus pyogenes FabT repressor controls fatty acid synthesis (FASII). FabT defects reduce virulence but mutants emerge, thriving in lipid-rich environments while failing in host tissues due to energy dissipation.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- The type II fatty acid synthesis pathway (FASII) in Streptococcus pyogenes is regulated by the FabT repressor.
- FabT repressor binds to acyl-Acyl carrier protein to control FASII.
- FabT defects have been linked to reduced virulence in animal models, yet spontaneous fabT mutants emerge during infection.
Purpose of the Study:
- To investigate the conditions and mechanisms governing FabT activity and fabT mutant emergence.
- To resolve the paradox between FabT's role in virulence and the in vivo emergence of fabT mutants.
- To understand the implications of FabT defects on bacterial survival in different environments.
Main Methods:
- Characterization of fabT mutant phenotypes under varying growth conditions.
- Analysis of energy dissipation and metabolic consumption in fabT mutants.
- Assessment of bacterial membrane composition and fatty acid incorporation.
Main Results:
- FabT defects cause energy dissipation, limiting growth on human tissue products and explaining the need for FabT during infection.
- fabT mutants exhibit enhanced growth in saturated fatty acid-rich environments.
- Continued FASII activity in fabT mutants hinders saturated fatty acid incorporation in lipid-rich biotopes.
Conclusions:
- FabT is essential for virulence by preventing energy dissipation in nutrient-limited host environments.
- Emergence of fabT mutants is favored in lipid-rich biotopes due to altered fatty acid metabolism.
- FabT defects create a trade-off: improved survival in lipid-rich niches but a genetic disadvantage for infection.
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