mSystems (Apr 2023)
Convergent Within-Host Adaptation of Pseudomonas aeruginosa through the Transcriptional Regulatory Network
Abstract
ABSTRACT Bacteria adapt to their host by mutating specific genes and by reprogramming their gene expression. Different strains of a bacterial species often mutate the same genes during infection, demonstrating convergent genetic adaptation. However, there is limited evidence for convergent adaptation at the transcriptional level. To this end, we utilize genomic data of 114 Pseudomonas aeruginosa strains, derived from patients with chronic pulmonary infection, and the P. aeruginosa transcriptional regulatory network. Relying on loss-of-function mutations in genes encoding transcriptional regulators and predicting their effects through the network, we demonstrate predicted expression changes of the same genes in different strains through different paths in the network, implying convergent transcriptional adaptation. Furthermore, through the transcription lens we associate yet-unknown processes, such as ethanol oxidation and glycine betaine catabolism, with P. aeruginosa host adaptation. We also find that known adaptive phenotypes, including antibiotic resistance, which were identified before as achieved by specific mutations, are achieved also through transcriptional changes. Our study has revealed novel interplay between the genetic and transcriptional levels in host adaptation, demonstrating the versatility of the adaptive arsenal of bacterial pathogens and their ability to adapt to the host conditions in a myriad of ways. IMPORTANCE Pseudomonas aeruginosa causes significant morbidity and mortality. The pathogen's remarkable ability to establish chronic infections greatly depends on its adaptation to the host environment. Here, we use the transcriptional regulatory network to predict expression changes during adaptation. We expand the processes and functions known to be involved in host adaptation. We show that the pathogen modulates the activity of genes during adaptation, including genes implicated in antibiotic resistance, both directly via genomic mutations and indirectly via mutations in transcriptional regulators. Furthermore, we detect a subgroup of genes whose predicted changes in expression are associated with mucoid strains, a major adaptive phenotype in chronic infections. We propose that these genes constitute the transcriptional arm of the mucoid adaptive strategy. Identification of different adaptive strategies utilized by pathogens during chronic infection has major promise in the treatment of persistent infections and opens the door to personalized tailored antibiotic treatment in the future.
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