Small RNA promotes negative feedback of the master virulence regulator PhoP by repressing the PhoQ sensor enhancer UgtL in acidic pH

To cause disease, pathogens must express their virulence genes at the right time and in proper levels. Here, we establish that a small RNA (sRNA) restricts the activation of a regulator critical for the virulence of <i>Salmonella enterica</i> serovar Typhimurium (<i>S.</i> Typhimurium). We show that the sRNA PinT inhibits the activity of the master virulence regulator PhoP by repressing its activator UgtL through a direct interaction with <i>ugtL</i> mRNA. This regulation reduces the expression of PhoP-activated genes. Because PhoP activates PinT and UgtL, the three regulators form a negative feedback loop. That the PinT-mediated repression of <i>ugtL</i> is predicted to occur in <i>Salmonella enterica</i> but not in the nonpathogenic species <i>S.</i> bongori suggests it may be a key virulence determinant. Our results unveil a novel layer of fine-tuning of PhoP activity ensuring that <i>S.</i> Typhimurium induces the proper level of its virulence program in response to an infection-relevant stress condition.