Emergence of a Pseudomonas aeruginosa Hypermutator Strain During the Course of Ventilator-Associated Pneumonia
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Abstract
Hypermutator lineages of Pseudomonas aeruginosa arise frequently during the years of lung infection seen in patients with cystic fibrosis and bronchiectasis but are rare in the absence of structural lung disease. Since the onset of the COVID-19 pandemic, large numbers of patients have remained mechanically ventilated for extended periods of time. These patients are prone to acquire bacterial pathogens that persist for many weeks and have the opportunity to evolve within the pulmonary environment. However, little is known about what types of adaptations occur in these bacteria and whether these adaptations mimic those described in chronic infections. We describe a COVID-19 patient with a secondary Pseudomonas aeruginosa lung infection in which the causative bacterium persisted for >90 days. During the course of this infection, a hypermutator lineage of P. aeruginosa emerged and co-existed with a non-hypermutator lineage. Compared to the parental lineage, the hypermutator lineage evolved to be more extensively resistant to antibiotics, to change its type III secretion profile, and to grow more slowly. Genomic analyses of the hypermutator lineage identified numerous mutations, including in the mismatch repair gene mutL and other genes frequently mutated in individuals with cystic fibrosis. Together, these findings demonstrate that hypermutator phenotypes can emerge when clearance of P. aeruginosa fails to occur in typically acute infections such as ventilator-associated pneumonia and suggest that hypermutator lineages can affect patient treatments and outcomes.
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SciScore for 10.1101/2022.05.19.22275029: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was approved by the Northwestern University Institutional Review Board (IRB). Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources a, GA) for 1 hr at room temperature and then exposed to a 1:2,000 concentration of polyclonal anti-ExoU antibodies overnight at 4°C on a slow rocker (29). anti-ExoUsuggested: NoneThe membrane was washed three times with 1x TBS-T at room temperature and then exposed to a goat anti-rabbit secondary antibody (LI-COR Biosciences, Lincoln, NE) at a 1:5,000 concentration in 20 mL of 5% milk buffer in 1x TBS-T for 1 hr at room temperature. anti-rabbitSciScore for 10.1101/2022.05.19.22275029: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was approved by the Northwestern University Institutional Review Board (IRB). Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources a, GA) for 1 hr at room temperature and then exposed to a 1:2,000 concentration of polyclonal anti-ExoU antibodies overnight at 4°C on a slow rocker (29). anti-ExoUsuggested: NoneThe membrane was washed three times with 1x TBS-T at room temperature and then exposed to a goat anti-rabbit secondary antibody (LI-COR Biosciences, Lincoln, NE) at a 1:5,000 concentration in 20 mL of 5% milk buffer in 1x TBS-T for 1 hr at room temperature. anti-rabbitsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources For certain experiments, P. aeruginosa strains PA14, PA14exoU, and PAO1 were used as controls. P. aeruginosasuggested: NoneSoftware and Algorithms Sentences Resources Sequences were trimmed using Trimmomatic v0.32 (17) and then de novo assembly was performed with SPAdes 3.9.1. Trimmomaticsuggested: (Trimmomatic, RRID:SCR_011848)Illumina reads were aligned to the assembly using BWA v0.7.17 (21), and assembly errors were corrected using Pilon v1.23 (22) with a minimum depth setting of 0.1. BWAsuggested: (BWA, RRID:SCR_010910)Pilonsuggested: (Pilon , RRID:SCR_014731)Single nucleotide variants relative to the reference were identified using bcftools v1.9 skipping bases with base quality lower than 25, alignment quality less than 30, and using a haploid model. bcftoolssuggested: (SAMtools/BCFtools, RRID:SCR_005227)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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