Abstract
Pathogenic bacteria often damage tissues by secreting toxins that form pores in cell membranes, and the most common pore-forming toxins are cholesterol-dependent cytolysins. During bacterial infections, glutamine becomes a conditionally essential amino acid, and glutamine is an important nutrient for immune cells. However, the role of glutamine in protecting tissue cells against pore-forming toxins is unclear. Here we tested the hypothesis that glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins. Stromal and epithelial cells were sensitive to damage by the cholesterol-dependent cytolysins, pyolysin and streptolysin O, as determined by leakage of potassium and lactate dehydrogenase from cells, and reduced cell viability. However, glutamine deprivation increased the leakage of lactate dehydrogenase and reduced the viability of cells challenged with cholesterol-dependent cytolysins. Without glutamine, stromal cells challenged with pyolysin leaked lactate dehydrogenase (control vs. pyolysin, 2.6 ± 0.6 vs. 34.4 ± 4.5 AU, n = 12), which was more than three-fold the leakage from cells supplied with 2 mM glutamine (control vs. pyolysin, 2.2 ± 0.3 vs. 9.4 ± 1.0 AU). Glutamine cytoprotection did not depend on glutaminolysis, replenishing the Krebs cycle via succinate, changes in cellular cholesterol, or regulators of cell metabolism (AMPK and mTOR). In conclusion, although the mechanism remains elusive, we found that glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins from pathogenic bacteria.
Highlights
Animals defend themselves against bacterial infections using the complimentary strategies of resistance and tolerance [1,2,3]
HeLa cells are sensitive to streptolysin O (SLO) [33, 34], and we found that glutamine deprivation increased lactate dehydrogenase (LDH) leakage when HeLa cells were challenges with SLO (Fig 6C; two-way ANOVA, P < 0.001)
First we showed that glucose was used by the cells for energy because inhibiting glycolysis, using 2-deoxy-D-glucose [9], markedly increased LDH leakage from stromal cells challenged with pyolysin, when cells were supplied with 2 mM glutamine (Fig 7A)
Summary
Animals defend themselves against bacterial infections using the complimentary strategies of resistance and tolerance [1,2,3]. Resistance is the ability to limit the pathogen burden, usually by employing the immune system to kill bacteria. Tolerance is the ability to limit the severity of disease caused by the pathogen burden, usually by limiting the damage caused by bacteria. Glutamine cytoprotection against cytolysins and the most common pore-forming toxins are cholesterol-dependent cytolysins [4,5,6,7]. The cells of the immune system use glutamine as a key nutrient to support inflammatory responses [8,9,10]. The role of glutamine in protecting tissue cells against the damage caused by cholesterol-dependent cytolysins is unclear
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