Cytotoxic necrotizing factor type 1 production by uropathogenic Escherichia coli modulates polymorphonuclear leukocyte function.
Many strains of uropathogenic Escherichia coli (UPEC) produce cytotoxic necrotizing factor type 1 (CNF1), a toxin that constitutively activates the Rho GTPases RhoA, Rac1, and Cdc42. We previously showed that CNF1 contributes to the virulence of UPEC in a mouse model of ascending urinary tract infection and a rat model of acute prostatitis and that a striking feature of the histopathology of the mouse bladders and rat prostates infected with CNF1-positive strains is an elevation in levels of polymorphonuclear leukocytes (PMNs). We also found that CNF1 synthesis leads to prolonged survival of UPEC in association with human neutrophils. Here, we tested the hypothesis that CNF1 production by UPEC diminishes the antimicrobial capacity of mouse PMNs by affecting phagocyte function through targeting Rho family GTPases that are critical to phagocytosis and the generation of reactive oxygen species. We found that, as with human neutrophils, CNF1 synthesis provided a survival advantage to UPEC incubated with mouse PMNs. We also observed that CNF1-positive UPEC down-regulated phagocytosis, altered the distribution of the complement receptor CR3 (CD11b/CD18), enhanced the intracellular respiratory burst, and increased levels of Rac2 activation in PMNs. From these results, we conclude that modulation of PMN function by CNF1 facilitates UPEC survival during the acute inflammatory response.
Davis
Jon M
JM
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, B4052, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
Rasmussen
Susan B
SB
O'Brien
Alison D
AD
D000818:Animals; D001427:Bacterial Toxins; D004926:Escherichia coli / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000382:microbiology* / Q000473:pathology / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D016897:Respiratory Burst / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C060296:cytotoxic necrotizing factor type 1