The role of the Pseudomonas aeruginosa hypermutator phenotype on the shift from acute to chronic virulence during respiratory infection

Abstract

Chronic respiratory infection (CRI) with Pseudomonas aeruginosa (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 mutS, mutL, and uvrD. In vitro and in vivo 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 mucA 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 retS, bfmS, and ampR, 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 lasR. 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.

Pathogenesis ofAchromobacter xylosoxidansrespiratory infections: colonization and persistence of airway epithelia and differential gene expression in synthetic cystic fibrosis sputum medium

“…This is well studied in Pseudomonas aeruginosa (Pa) and is understood to contribute to differential gene expression in strains that are chronic colonizers (19)(20)(21). Hypermutation occurs due to mutation in mismatch repair systems that allow for bacteria to rapidly mutate genes and respond to selective pressure (20). Although it is not well-studied in Ax, hypermutation has been observed in this species and may be a factor that contributes to the discrepancies between genotype and phenotype that we have observed here (22,23).…”

“…This discrepancy between genotype and phenotype may be explained by a phenomenon known as hypermutation. This is well studied in Pseudomonas aeruginosa (Pa) and is understood to contribute to differential gene expression in strains that are chronic colonizers (19)(20)(21). Hypermutation occurs due to mutation in mismatch repair systems that allow for bacteria to rapidly mutate genes and respond to selective pressure (20).…”

Rapid evolution bacteria reveal pathogenic mechanisms and clinical risk

“…However, controversial observations have also been reported indicating that hypermutator strains are less virulent than wild-type P. aeruginosa 37,38 . Therefore, it is necessary to establish a method that allows us to observe bacterial evolution in cohorts over a speci c study period to gain a better understanding of the role of mutation frequency in bacterial infection 39,40 .…”

Functionality of chimeric TssA proteins in the type VI secretion system involves sheath docking specificty

“…Pseudomonas aeruginosa is a ubiquitous, opportunistic gram-negative bacterial pathogen, responsible for acute and chronic infections 23,24 , including in the lungs and airways of cystic fibrosis patients 25 . Remarkably, there are three T6SS clusters within the P. aeruginosa genome (H1-, H2-and H3-T6SS) 26,27 , each encoding all the core structural components required to assemble a functional T6SS (tssA-M).…”