Abstract
Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs), inducing acute pyelonephritis and may result in permanent renal scarring and failure. Alpha-hemolysin (HlyA), a key UPEC toxin, causes serious tissue damage; however, the mechanism through which HlyA induces kidney injury remains unclear. In the present study, granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by renal epithelial cells was upregulated by HlyA in vitro and in vivo, which induced M1 macrophage accumulation in kidney, and ADAM10 was found involved in HlyA-induced GM-CSF. Macrophage elimination or GM-CSF neutralization protected against acute kidney injury in mice, and increased GM-CSF was detected in urine of patients infected by hlyA-positive UPEC. In addition, HlyA was found to promote UPEC invasion into renal epithelial cells by interacting with Nectin-2 in vitro. However, HlyA did not affect bacterial titers during acute kidney infections, and HlyA-induced invasion did not contribute to GM-CSF upregulation in vitro, which indicate that HlyA-induced GM-CSF is independent of bacteria invasion. The role of GM-CSF in HlyA-mediated kidney injury may lead to novel strategies to treat acute pyelonephritis.
Highlights
Urinary tract infections (UTIs), which are one of the most common infectious diseases, affect >100 million people annually worldwide.[1]
While there was no difference in infiltrated neutrophils, significantly more macrophages were detected in the CFT073 or ΔhlyA p-hlyA group compared with the ΔhlyA group (Fig. 1c and Supplementary Fig. S1d)
We examined bacterial titers in kidneys of C57BL/6J mice at 12, 24, and 48 hpi with CFT073, ΔhlyA, or ΔhlyA p-hlyA, and no statistically significant difference was observed (Fig. 1d). These results indicate that HlyA induces kidney injury and increases macrophages during acute kidney infections, which is independent of bacterial titers at the point in time we observe
Summary
Urinary tract infections (UTIs), which are one of the most common infectious diseases, affect >100 million people annually worldwide.[1]. Virulence factors of UPEC that contribute to pathogenesis of UTIs mainly include fimbriae involved in adherence and invasion to host cells, toxins affecting host cells, and iron-acquisition systems for bacterial growth.[3,5] Alpha-hemolysin of UPEC, HlyA, is cytotoxic to a wide range of cells and causes serious tissue damage during UTIs.[6] The hlyA gene is located in the operon, including hlyC, hlyA, hlyB, and hlyD. HlyC is an acyltransferase that activates HlyA, and HlyB and HlyD are involved in HlyA secretion.[7] HlyA is reported to induce kidney inflammation and injury,[5,8] and a higher percentage of hlyA-positive strains are isolated from pyelonephritis patients ( > 70%) than from cystitis patients (31–48%), implying that HlyA is an important virulence factor in pyelonephritis.[7] In vitro studies have shown that HlyA lyses cells by forming pores on cell membrane at high concentrations;[6,7]
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