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.