Abstract
Bacterial persister cells are highly tolerant to antibiotics and cause chronic infections. However, little is known about the interaction between host immune systems with this subpopulation of metabolically inactive cells, and direct effects of host immune factors (in the absence of immune cells) on persister cells have not been studied. Here we report that human granulocyte macrophage-colony stimulating factor (GM-CSF) can sensitize the persister cells of Pseudomonas aeruginosa PAO1 and PDO300 to multiple antibiotics including ciprofloxacin, tobramycin, tetracycline, and gentamicin. GM-CSF also sensitized the biofilm cells of P. aeruginosa PAO1 and PDO300 to tobramycin in the presence of biofilm matrix degrading enzymes. The DNA microarray and qPCR results indicated that GM-CSF induced the genes for flagellar motility and pyocin production in the persister cells, but not the normal cells of P. aeruginosa PAO1. Consistently, the supernatants from GM-CSF treated P. aeruginosa PAO1 persister cell suspensions were found cidal to the pyocin sensitive strain P. aeruginosa PAK. Collectively, these findings suggest that host immune factors and bacterial persisters may directly interact, leading to enhanced susceptibility of persister cells to antibiotics.
Highlights
First defined in 1940 s1, persister cells are a small fraction of metabolically inactive bacterial cells that are phenotypic variants and are highly tolerant to antibiotics and other environmental stresses
The presence of persister cells is evidenced by biphasic killing by antibiotics, which has a rapid killing of normal cells and a plateau with surviving persisters irresponsive to very high concentrations of antibiotics even with prolonged treatment
This was observed for P. aeruginosa PAO1, PDO300, E. coli K12, and E. coli ATCC 53505 cells isolated from both exponential and stationary phase cultures (Supplementary Fig. S1), confirming the presence of persister cells in our experimental conditions
Summary
First defined in 1940 s1, persister cells are a small fraction (normally less than 1% of the total population) of metabolically inactive bacterial cells that are phenotypic variants and are highly tolerant to antibiotics and other environmental stresses. When the persister cells of PA0620::phoA, an isogenic deletion mutant of PA0620 encoding the R2-pyocin tail fiber protein, were treated with 0.17 pM or 0.17 nM GM-CSF, the supernatants did not change the viability of P. aeruginosa PAO1 and PAK (Fig. 7b).
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