Structural and functional insights into Pseudomonas aeruginosa's secretion systems 1-6: regulation, role in microbial...

Pseudomonas aeruginosa is a versatile Gram-negative pathogen that thrives in diverse environments. This pathogen causes a range of infections, including microbial keratitis (MK), a sight-threatening corneal infection. Central to its virulence are six specialized protein secretion systems (Types 1-6) that span the complex cell envelope. One-step systems (Types 1, 3, 4, 6) directly translocate effectors across both of its cell membranes, while two-step systems (Types 2, 5) first export substrates into the periplasm via the Sec or Tat pathways before outer-membrane release. These molecular machines deliver toxins, enzymes and competitive effectors that facilitate tissue damage, immune evasion, nutrient acquisition, biofilm formation and interbacterial killing. Their expression and activity are often coordinated by quorum-sensing networks (Las, Rhl, Pqs, Iqs). Although various secretion systems and their effectors have been characterized, the specific contributions of each system to corneal infection have yet to be comprehensively reviewed.

PubMed and Google Scholar were searched to synthesize current knowledge of the structure, regulation, and substrates of these secretion systems, to highlight their contributions to keratitis pathogenesis, and to evaluate emerging anti-virulence strategies targeting these pathways as novel therapeutics.

The T3SS system and its effectors ExoU and ExoS play dominant roles in keratitis severity while other secretion systems further enhance virulence by facilitating toxin release, biofilm development, and interbacterial competition. Regulatory interactions with quorum-sensing pathways amplify their impact during infection.

Understanding the functional roles of all six secretion pathways and their regulatory mechanisms will be critical for identifying and developing novel anti-virulence therapeutics for MK.