Table 1.

Bacterial factors/complex involved in host-adaptation during chronic PA infections.

Bacterial factor/complex	Bacterial function	Host interactions	Adaptation in chronic infection
Flagellum	- Macromolecular motility appendage which confers motility in low viscosity liquids through rotational movement - Flagellin is the principal structural component of the flagellar filament - Mediates biotic and abiotic surface adhesion	- Flagellin binds and activates TLR5 and intracellular Naip5 protein, leading to activation of MyD88 and NLRC4—dependent inflammatory pathways respectively - Promotes surface attachment and colonization by adhering to mucins, surfactant protein A, host surface molecules (e.g., heparin sulfate proteoglycans, AsialoGM1)	- Reduced flagellar motility and/or flagellin synthesis in response to mucin, neutrophil elastase and airway fluid, during biofilm growth, and due to genetic mutations in biogenesis or regulatory genes (e.g., rpoN, fleQ) - Dampened host recognition, phagocytic uptake and downstream activation of MyD88 and NLRC4—dependent pathways
Type IV pili (T4P)	- Macromolecular motility appendage which confers surface motility through extension, attachment, and retraction movement - Mediates sensing and adhesion to biotic and abiotic surfaces - Promotes biofilm formation (in vitro) - DNA uptake	- Binds host surface molecules (e.g., heparin sulfate proteoglycans and N-glycans) and promotes surface colonization - Promotes direct bacterial-host cell membrane contact and thus T3SS-dependent toxicity	- Reduced pilus-mediated motility due to regulatory control (e.g., cAMP and cyclic-di-GMP pathways) or due genetic mutations in biogenesis or regulatory genes - Reduced colonization and invasion of host tissues
Type 3 secretion system (T3SS)	- Needle-like structure that injects and translocates bacterial effector proteins across cellular membranes into the host cell cytoplasm	- Translocation of effectors proteins (ExoU, ExoY, ExoS, ExoT, flagellin) which interact with the eukaryotic cytoskeleton and immune responses in phagocytes and non-phagocytic cells - Translocation of flagellin and other flagellar components into host cytosol, leading to inflammasome activation	- Repressed expression due to regulatory control or mutations of regulatory genes (e.g., RetS/GacS, cyclic-di-GMP pathways) - Reduced host cell cytotoxicity and inflammasome activation
Type 6 secretion system (T6SS)	- Secretion/injection system that delivers effector proteins into prokaryotic and eukaryotic target cells - Involved in bacterial competition	- The effectors PldA and PldB activate the PI3K/Akt pathway, and VgrG2b interacts with microtubules, which promote bacterial internalization in non-phagocytic cells (in vitro)	- Expression potentially induced due to regulatory control or mutations of regulatory genes (e.g., RetS/GacS, cyclic-di-GMP pathways)
Exopolysaccharides	- Alginate scavenges reactive oxygen species and is overproduced in mucoid variants - Psl and Pel have aggregative properties that confer cell-cell and surface adherence - Major structural component of biofilm matrix, which contribute to biofilm antibiotic resistance	- Pel and Psl promotes adherence to host cell surface - Interferes with opsono-phagocytosis, phagocyte oxidative burst and killing	- EPS overproduction due to mutations or environment control in regulatory genes (e.g., mucA, cyclic-d-GMP pathway) - Co-regulation of EPS with other bacterial factors through common pathways (e.g., AlgT, cyclic-di-GMP) leads to repression of flagellar biosynthesis and T3SS activity, increased expression of bacterial lipoproteins (TLR2 agonists) in EPS over-expressing strains. - Impaired bacterial clearance
Lipolysaccharides (LPS)	- Lipid A component is embedded in the outer membrane - O-antigen is composed of highly variable oligosaccharide repeats exposed at the bacterial surface	- Lipid A binds TLR4-MD2 - O-antigen is a common antibody epitope - Confers resistance to complement killing and cationic antimicrobial peptides	- Different lipid A modifications with varying impact: enhanced or dampened TLR4 activation, leading to immune evasion or enhanced immune-stimulation - Loss of O-antigen due to mutations in biosynthetic genes, leading to immune evasion
Secreted proteases (LasA, LasB, AprA, Protease IV)	- Proteolytic degradation of extracellular peptides	- Degrades elastin, thrombin, fibrinogen, surfactant proteins A and D, complements proteins, immunoglobulins, cytokines, and other extracellular mediators - Degrades flagellin - Disrupts epithelial tight-junctions and reduces barrier integrity	- Loss of secreted protease activity due to genetic mutations in regulatory genes (e.g., LasR quorum sensing) - Reduced host tissue destruction and invasion - Dampened immune recognition - Increased accumulation of mediators and inflammation