Mediators of infection in the Pseudomonas aeruginosa accessory genome

Project: Research project

Project Details

Description

Background: Bacterial infections in patients with cancer undergoing cytotoxic chemotherapy or stem-cell transplantation remain a source of considerable morbidity and mortality in this population. Further complicating these infections is the growing prevalence of antibiotic resistance limiting the effectiveness of current treatments and driving the search for novel and directed antimicrobials. The net result is that many patients who would otherwise survive their cancers succumb to infections. The bacterium Pseudomonas aeruginosa (PA) is responsible for a large proportion of these infections, underscoring the need to better understand its pathogenesis. Accessory genomic elements (AGEs), regions of DNA present in some strains of an organism but not others, are thought to comprise 10% of the PA genome, but their roles in modulating virulence remain underexplored. Prior studies have identified AGEs in PA that enhance the severity of pneumonia in animal models. The purpose of the proposed research is to identify novel virulence factors carried in the accessory genome of PA that can be targeted to improve outcomes in patients with PA infections, including those with malignancies.
Objective/Hypothesis: This study hypothesizes that AGEs of PA are a source of previously uncharacterized virulence determinants.
Specific Aims: (1) Obtain genomic sequences of 35 PA pneumonia isolates to identify AGEs. Identify candidate elements with a high likelihood of encoding pathogenicity determinants. (2) Test these candidate elements to identify novel virulence genes that enhance the severity of respiratory infections.
Study Design: The genomes of a panel of PA clinical isolates from patients with ventilator-associated pneumonia will be sequenced. AGEs will be identified through exclusion of sequences that align to the core genome of PA. The distribution of these genomic elements among the panel of isolates will be determined to evaluate for association of certain AGEs with highly virulent strains. Predicted genes in the genomic elements will also be screened for similarities to known bacterial virulence factors or possible virulence-associated systems. Through deletion of virulence-associated AGEs from highly virulent strains and conjugation of elements into less-virulent strains, their effect on PA pathogenicity will be examined in a mouse model of pneumonia. A process of stepwise deletions of these AGEs will be undertaken to identify specific genes within each element responsible for the virulence effects.
StatusFinished
Effective start/end date7/1/1312/31/18

Funding

  • American Cancer Society (MRSG-13-220-01 - MPC)

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