Contribution of two-component regulatory systems to the acute-to-chronic infection transition of <i>Pseudomonas aeruginosa</i> in cystic fibrosis

Cystic fibrosis (CF) is a life-threatening genetic disorder that causes severe dysfunction in the lungs, digestive system, and other organs. Chronic respiratory infections are a significant cause of morbidity and mortality among CF-related complications. <i>Pseudomonas aeruginosa</i> is an opportunistic bacterial pathogen and a predominant colonizer of the CF lung. It drives a progressive decline in pulmonary function. This pathogen shows remarkable adaptability. It can establish both acute and chronic infections despite the host's immune defenses and antimicrobial treatments. <i>P. aeruginosa</i> expresses a diverse set of virulence factors, including adhesins, proteases, exotoxins, siderophores, secretion systems, and exopolysaccharides. These factors facilitate host colonization, immune evasion, and disease progression. The transition from acute to chronic infection is mediated by bacterial sensing of environmental signals. These signals dynamically modulate the expression of virulence factors. Also, the hostile conditions within the CF lung drive the acquisition and accumulation of adaptive mutations in the bacterial genome. These genetic modifications often impair the efficiency of DNA repair mechanisms, leading to a hypermutable phenotype. This accelerates bacterial evolution. As a result, acute-phase virulence factors are downregulated, while antimicrobial resistance and biofilm formation increase. This contributes to persistent and refractory infections. In this review, we examine the crucial roles of two-component regulatory systems. These systems fine-tune gene expression, enhance bacterial survival, and regulate the shift from acute to chronic infection. Understanding these adaptive mechanisms is essential for developing novel therapeutic strategies to combat this highly resilient pathogen.