Borisova Dayana, Paunova-Krasteva Tsvetelina, Strateva Tanya, Stoitsova Stoyanka
Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 25, 1113 Sofia, Bulgaria.
Department of Medical Microbiology "Corr. Mem. Prof. Ivan Mitov, MD, DMSc", Faculty of Medicine, Medical University of Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria.
Microorganisms. 2025 Jun 30;13(7):1527. doi: 10.3390/microorganisms13071527.
Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting a large number of individuals in Europe. The disease arises from mutations in the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator, a chloride ion channel crucial for maintaining epithelial ion and fluid homeostasis. Dysfunctional CFTR disrupts mucociliary clearance, particularly in the respiratory tract, resulting in persistent bacterial colonization, chronic inflammation, and progressive pulmonary damage-ultimately leading to respiratory failure, the principal cause of mortality in CF patients. Early diagnosis and advances in therapy have substantially improved both survival and quality of life. A hallmark of CF pathology is the establishment of polymicrobial infections within the thickened airway mucus. is the dominant pathogen in chronic CF lung infections and demonstrates a remarkable capacity for adaptation via biofilm formation, metabolic reprogramming, and immune evasion. Biofilms confer increased tolerance to antimicrobial agents and facilitate long-term persistence in hypoxic, nutrient-limited microenvironments. exhibits a wide range of virulence factors, including exotoxins (e.g., ExoU, ExoS), pigments (pyoverdine, pyochelin), and motility structures (flagella and pili), which contribute to tissue invasion, immune modulation, and host damage. During chronic colonization, undergoes significant genotypic and phenotypic changes, such as mucoid conversion, downregulation of acute virulence pathways, and emergence of hypermutator phenotypes that facilitate rapid adaptation. Persistent cells, a specialized subpopulation characterized by metabolic dormancy and antibiotic tolerance, further complicate eradication efforts. The dynamic interplay between host environment and microbial evolution underlies the heterogeneity of CF lung infections and presents significant challenges for treatment. Elucidating the molecular mechanisms driving persistence, hypermutability, and biofilm resilience is critical for the development of effective therapeutic strategies targeting chronic infections in CF.
囊性纤维化（CF）是一种危及生命的常染色体隐性疾病，影响着欧洲大量人群。该疾病源于编码囊性纤维化跨膜传导调节因子（CFTR）的基因突变，CFTR是一种氯离子通道，对维持上皮离子和液体稳态至关重要。功能失调的CFTR会破坏黏液纤毛清除功能，尤其是在呼吸道，导致持续性细菌定植、慢性炎症和进行性肺损伤，最终导致呼吸衰竭，这是CF患者死亡的主要原因。早期诊断和治疗进展显著提高了生存率和生活质量。CF病理学的一个标志是在增厚的气道黏液中形成多种微生物感染。铜绿假单胞菌是慢性CF肺部感染的主要病原体，通过生物膜形成、代谢重编程和免疫逃避表现出显著的适应能力。生物膜赋予对抗菌剂的耐受性增加，并有助于在缺氧、营养有限的微环境中长期存活。铜绿假单胞菌表现出广泛的毒力因子，包括外毒素（如ExoU、ExoS）、色素（绿脓菌素、螯铁菌素）和运动结构（鞭毛和菌毛），这些有助于组织侵袭、免疫调节和宿主损伤。在慢性定植期间，铜绿假单胞菌会发生显著的基因型和表型变化，如黏液样转化、急性毒力途径下调以及促进快速适应的高突变体表型的出现。持久细胞是一种以代谢休眠和抗生素耐受性为特征的特殊亚群，进一步使根除工作复杂化。宿主环境与微生物进化之间的动态相互作用是CF肺部感染异质性的基础，并给治疗带来重大挑战。阐明驱动持久性、高突变性和生物膜弹性的分子机制对于开发针对CF中慢性铜绿假单胞菌感染的有效治疗策略至关重要。
