Alpha-hemolysin of uropathogenic Escherichia coli induces GM-CSF-mediated acute kidney injury

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.

Protective Role of Nrf2 in Renal Disease

“…Sepsis is one of the factors that trigger AKI in intensive care patients [ 139 ] and the pathogenic endotoxin LPS is the most important factor responsible for its occurrence [ 140 ]. LPS has been described both as a ROS producer and a blocking agent of the antioxidant response that finally leads to AKI, downregulating the production of CAT, SOD, and GSH as well as the Nrf2 signaling pathway [ 141 , 142 ].…”

Bacterial pore-forming toxins

“…HlyA additionally promotes proteolysis of several host proteins involved in adhesion, stimulating invasion [134]. In renal epithelial cells HlyA induces production of granulocyte-macrophage colony-stimulating factor (GM-CSF), thereby driving accumulation of M1 macrophages and leading to kidney injury [56].…”

Nucleotide receptors mediate protection against neonatal sepsis and meningitis caused by alpha‐hemolysin expressing Escherichia coli K1

“…It is surprising that NMEC RS218, which harbors both HlyA and CNF-1, is less virulent than the nontoxin-producing NMEC O18, as both these toxins are associated with increased disease severity during UPEC infection. 19,20,50 We hypothesized that HlyA and/or CNF-1 may trigger protective innate immune pathways which contribute to the enhanced bacterial clearance of NMEC RS218 compared to NMEC O18. CNF-1 has been shown to facilitate NMEC crossing of the BBB; however, it is also known to increase nonspecific endocytosis of material by macrophages.…”

“…18 HlyA is a pore-forming toxin harbored by approximately 30% of NMEC isolates, 3 and has also been associated with increased severity of uropathogenic E. coli (UPEC) infection. 19,20 HlyA interacts with several immune pathways, including the NLRP3 inflammasome and purinergic receptor pathways, in the context of UPEC infection. [21][22][23][24][25] While these interactions could contribute to increased pathogenicity of HlyA + bacteria, under certain conditions they may also induce protective immune responses that improve bacterial clearance.…”