Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States.
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, United States.
Front Cell Infect Microbiol. 2022 Jul 22;12:943346. doi: 10.3389/fcimb.2022.943346. eCollection 2022.
Chronic respiratory infection (CRI) with (Pa) presents many unique challenges that complicate treatment. One notable challenge is the hypermutator phenotype which is present in up to 60% of sampled CRI patient isolates. Hypermutation can be caused by deactivating mutations in DNA mismatch repair (MMR) genes including , , and . and studies have demonstrated hypermutator strains to be less virulent than wild-type Pa. However, patients colonized with hypermutators display poorer lung function and a higher incidence of treatment failure. Hypermutation and MMR-deficiency create increased genetic diversity and population heterogeneity due to elevated mutation rates. MMR-deficient strains demonstrate higher rates of mucoidy, a hallmark virulence determinant of Pa during CRI in cystic fibrosis patients. The mucoid phenotype results from simple sequence repeat mutations in the gene made in the absence of functional MMR. Mutations in Pa are further increased in the absence of MMR, leading to microcolony biofilm formation, further lineage diversification, and population heterogeneity which enhance bacterial persistence and host immune evasion. Hypermutation facilitates the adaptation to the lung microenvironment, enabling survival among nutritional complexity and microaerobic or anaerobic conditions. Mutations in key acute-to-chronic virulence "switch" genes, such as , , and , are also catalyzed by hypermutation. Consequently, strong positive selection for many loss-of-function pathoadaptive mutations is seen in hypermutators and enriched in genes such as . This results in the characteristic loss of Pa acute infection virulence factors, including quorum sensing, flagellar motility, and type III secretion. Further study of the role of hypermutation on Pa chronic infection is needed to better inform treatment regimens against CRI with hypermutator strains.
慢性呼吸道感染（CRI）伴（Pa）存在许多独特的挑战，使治疗变得复杂。一个显著的挑战是高达 60%的 CRI 患者分离株存在的高突变表型。突变可由 DNA 错配修复（MMR）基因失活突变引起，包括、和。和研究表明，高突变株比野生型 Pa 的毒力更低。然而，定植高突变株的患者肺功能较差，治疗失败的发生率更高。高突变和 MMR 缺陷导致由于突变率升高而增加遗传多样性和种群异质性。MMR 缺陷株表现出更高的黏液性，这是囊性纤维化患者 CRI 期间 Pa 的一个重要毒力决定因素。黏液表型是由于在缺乏功能性 MMR 的情况下在基因中发生简单序列重复突变而导致的。在缺乏 MMR 的情况下，Pa 中的突变进一步增加，导致微菌落生物膜形成、进一步的谱系多样化和种群异质性，从而增强了细菌的持久性和宿主免疫逃避。高突变促进了对肺部微环境的适应，使细菌能够在营养复杂性以及微需氧或厌氧条件下生存。关键的急性到慢性毒力“开关”基因如、和的突变也被高突变催化。因此，在高突变体中观察到许多功能丧失的适应性突变的强烈正选择，并且在基因如中富集。这导致 Pa 急性感染毒力因子的特征性丧失，包括群体感应、鞭毛运动和 III 型分泌。需要进一步研究高突变对 Pa 慢性感染的作用，以更好地为针对高突变株 CRI 的治疗方案提供信息。
