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Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation
Anna Waldhuber, … , Catharina Svanborg, Thomas Miethke
Anna Waldhuber, … , Catharina Svanborg, Thomas Miethke
Published May 23, 2016
Citation Information: J Clin Invest. 2016;126(7):2425-2436. https://doi.org/10.1172/JCI81916.
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Research Article Immunology

Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation

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Abstract

Successful bacterial pathogens produce an array of virulence factors that allow subversion of the immune system and persistence within the host. For example, uropathogenic Escherichia coli strains, such as CFT073, express Toll/IL-1 receptor–containing (TIR-containing) protein C (TcpC), which impairs TLR signaling, thereby suppressing innate immunity in the urinary tract and enhancing persistence in the kidneys. Here, we have reported that TcpC also reduces secretion of IL-1β by directly interacting with the NACHT leucin-rich repeat PYD protein 3 (NLRP3) inflammasome, which is crucial for recognition of pathogens within the cytosol. At a low MOI, IL-1β secretion was minimal in CFT073-infected macrophages; however, IL-1β release was markedly increased in macrophages infected with CFT073 lacking tcpC. Induction of IL-1β secretion by CFT073 and tcpC–deficient CFT073 required the NLRP3 inflammasome. TcpC attenuated activation of the NLRP3 inflammasome by binding both NLRP3 and caspase-1 and thereby preventing processing and activation of caspase-1. Moreover, in a murine urinary tract infection model, CFT073 infection rapidly induced expression of the NLRP3 inflammasome in the bladder mucosa; however, the presence of TcpC in WT CFT073 reduced IL-1β levels in the urine of infected mice. Together, these findings illustrate how uropathogenic E. coli use the multifunctional virulence factor TcpC to attenuate innate immune responses in the urinary tract.

Authors

Anna Waldhuber, Manoj Puthia, Andreas Wieser, Christine Cirl, Susanne Dürr, Silke Neumann-Pfeifer, Simone Albrecht, Franziska Römmler, Tina Müller, Yunji Zheng, Sören Schubert, Olaf Groß, Catharina Svanborg, Thomas Miethke

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Figure 1

TcpC-mediated reduction of IL-1β secretion by innate immune cells upon infection with CFT073.

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TcpC-mediated reduction of IL-1β secretion by innate immune cells upon ...
We infected BMDMs (A–C), BMDCs (D and E), and HCV29 cells (F) with titrated amounts of CFT073, the tcpC-deficient strain CFT073 tcpC::kan, or the tcpC-complemented strain CFT073 tcpC::kan+pTcpC, as indicated. IL-1β was quantified in the culture supernatants after 3 hours of culture by ELISA (A, D, and F). Stimulation of cells with ATP plus LPS served as positive and the culture of cells in the absence of bacteria as negative control. Data represent mean of 2 (A), mean ± SD of 8 (D), and mean ± SD of 4 (F) individual cultures. A depicts a representative experiment out of 4. Culture supernatants (B and E) and the cytosol of host cells (C) were analyzed by Western blot to detect mature IL-1β, processed caspase-1, and NLRP3. β-actin served as loading control. *P < 0.05, 1-way ANOVA, post hoc Bonferroni’s multiple comparison test.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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