Intrinsic and Extrinsic Regulation of Type III Secretion Gene Expression in Pseudomonas Aeruginosa

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that is particularly problematic in the healthcare setting where it is a frequent cause of pneumonia, bloodstream, and urinary tract infections. An important determinant of P. aeruginosa virulence is a type III secretion system (T3SS). T3SS-dependent intoxication is a complex process that minimally requires binding of P. aeruginosa to host cells, injection of the cytotoxic effector proteins through the host cell plasma membrane, and induction of T3SS gene expression. The latter process, referred to as contact-dependent expression, involves a well-characterized regulatory cascade that activates T3SS gene expression in response to host cell contact. Although host cell contact is a primary activating signal for T3SS gene expression, the involvement of multiple membrane-bound regulatory systems indicates that additional environmental signals also play a role in controlling expression of the T3SS. These regulatory systems coordinate T3SS gene expression with many other cellular activities including motility, mucoidy, polysaccharide production, and biofilm formation. The signals to which the organism responds are poorly understood but many seem to be coupled to the metabolic state of the cell and integrated within a master circuit that assimilates informational signals from endogenous and exogenous sources. Herein we review progress toward unraveling this complex circuitry, provide analysis of the current knowledge gaps, and highlight potential areas for future studies. Complete understanding of the regulatory networks that control T3SS gene expression will maximize opportunities for the development of strategies to treat P. aeruginosa infections.

Keywords: ExsA; Pseudomonas aeruginosa; RsmA; Vfr; cAMP; gene regulation; injectisome; type III secretion.

Figure 1

Sequence alignment of ExsA-dependent promoters and working model for promoter recognition and recruitment of σ⁷⁰-RNAP by ExsA. Nucleotides in bold are highly conserved in all ExsA-dependent promoters and have been shown through mutagenesis and DNA-biding studies to be important for ExsA-dependent activation. The boxed sequences represent the -10 promoter recognition site. Predicted points of interaction for the helix-turn-helix (HTH) DNA-binding motifs of each ExsA monomer are indicated. Studies have shown that ExsA recruits σ⁷⁰-RNAP through interactions mediated by region 4.2 of σ⁷⁰. The ExsA consensus binding sequence is indicated at the bottom of the diagram.

Figure 2

Working model for inverse regulation of T3SS with mucoidy and biofilm formation. See text for details.