A comprehensive screening of the two-component network in Staphylococcus aureus

Abstract

The pathogenesis of Staphylococcus aureus (S. aureus) involves a complex interplay between the host environment and expression of virulence factors, such as cytolytic toxins. In this bacterium, the primary method of sensing environmental signals and adapting gene expression are two-component systems (TCS), which combine signal transduction into a membrane-bound histidine kinase (HK) and a cytosolic response regulator (RR). In S. aureus, several TCSs are well defined as core regulators of cytolytic activity, but a comprehensive understanding of this relationship in the entire network has eluded us as previous studies have been conducted in a wide range of strains and growth conditions. To overcome this, we screened cytolytic activity in a collection of transposon mutants of each TCS in the genome of S. aureus JE2. This identified several TCSs mutants with reduced cytolytic activity including the phoP mutant, a mutant in the RR of the phosphate sensing TCS, PhoRP. Further investigation of the phosphate system in S. aureus identified PitR, a regulatory protein in an operon with the PitA phosphate transporter, as a repressor of cytotoxicity. Moreover, we identified that the phoP mutant has higher cytotoxicity than JE2 under phosphate limiting conditions, suggesting PhoRP signalling represses cytotoxicity in these conditions. We hypothesis that this response is dependent on PhoRP sensing phosphate limitation and inducing expression of the pit operon, including PitR. Overall, this project uncovers a previously unknown link between phosphate homeostasis and cytotoxicity and establishes phosphate as an important environmental signal for coordinating the pathogenicity of S. aureus.

Date of Award	2 Dec 2021
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ruth C Massey (Supervisor)