The effect of Pseudomonas-released quinolones on the mTOR pathway and phagocytic bacterial killing

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  • February 26, 2019
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  • Lanahan, Stephen
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • Cystic fibrosis (CF) patients are immunocompromised and often suffer from polymicrobial infections involving Pseudomonas aeruginosa, an opportunistic bacterial pathogen. P. aeruginosa pathogenicity is influenced by the secretion of bacterial compounds such as quinolones. P. aeruginosa secretes at least 50 different quinolone-based molecules. Although two of these, PQS and HHQ, are signals for a bacterial quorum sensing system, there are no known roles for the majority of the quinolones. A third quinolone molecule, HQNO, is secreted at high levels in culture. Preliminary data using macrophages suggest that HQNO inhibits respiratory burst, the process by which eukaryotic cells kill phagocytosed bacteria with reactive oxygen. Respiratory burst is known to be regulated by the mammalian target of rapamycin pathway (mTOR). We hypothesize that HQNO inhibits mTOR and thus the ability of macrophages to kill bacteria such as P. aeruginosa and the secondary pathogen Burkholderia multivorans. We used western blotting to demonstrate that in HQNO-treated mouse embryonic fibroblasts (MEFs), phosphorylation of the mTOR inhibitor AMPK was increased, and phosphorylation of the downstream mTOR effector, S6 ribosomal protein was reduced, in a time and dose dependent manner. Next, we tested whether bacterial killing by RAW 264.7 macrophages depended on HQNO. We found that HQNO treatment decreased killing of P. aeruginosa and B. multivorans by RAW macrophage cells. HQNO more strongly suppresses the ability of macrophages to kill B. multivorans than P. aeruginosa. Thus, the production of P. aeruginosa quinolones may protect secondary pathogens, such as B. multivorans, during polymicrobial infection in CF patients.
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  • In Copyright
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  • Funding: National Institutes of Health, Cystic Fibrosis Foundation, UNC’s Summer Undergraduate Research Fellowship
Advisor
  • Maddox, Amy
Degree
  • Bachelor of Arts
Degree granting institution
  • University of North Carolina at Chapel Hill
Extent
  • 12

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