Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14

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Abstract

A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host's immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on mouse dendritic cells as a binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of the pathogenic strain CFT073 to CD14 reduced dendritic cell migration by overactivation of integrins and blunted expression of co-stimulatory molecules by overactivating the NFAT pathway, both rate-limiting factors of T cell activation. This response was binary at the single cell level, but averaged in larger populations exposed to both piliated and non-piliated pathogens, presumably via the exchange of immunomodulatory cytokines. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn's disease.

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Kathrin Tomasek

Institute of Science and Technology Austria, Klosterneuburg, Austria

For correspondence
kathrin.tomasek@epfl.ch

Competing interests
Kathrin Tomasek, is an inventor on patent application 21170193.3 (Methods determining the potential of drug for treating bacterial infections and composition for treating bacterial infections").".
Alexander Leithner

Institute of Science and Technology Austria, Klosterneuburg, Austria

Competing interests
No competing interests declared.
Ivana Glatzova

Institute of Science and Technology Austria, Klosterneuburg, Austria

Competing interests
No competing interests declared.
Michael Sebastian Lukesch

VALANX Biotech GmbH, Klosterneuburg, Austria

Competing interests
Michael Sebastian Lukesch, is affiliated with VALANX Biotech GmbH. The author has no financial interests to declare.Is an inventor on patent application 21170193.3 (Methods determining the potential of drug for treating bacterial infections and composition for treating bacterial infections").".
Calin C Guet

Institute of Science and Technology Austria, Klosterneuburg, Austria

For correspondence
calin.guet@ist.ac.at

Competing interests
Calin C Guet, is an inventor on patent application 21170193.3 (Methods determining the potential of drug for treating bacterial infections and composition for treating bacterial infections").".

"This ORCID iD identifies the author of this article:" 0000-0001-6220-2052
Michael Sixt

Institute of Science and Technology Austria, Klosterneuburg, Austria

For correspondence
sixt@ist.ac.at

Competing interests
Michael Sixt, is an inventor on patent application 21170193.3 (Methods determining the potential of drug for treating bacterial infections and composition for treating bacterial infections").".

"This ORCID iD identifies the author of this article:" 0000-0002-6620-9179

Funding

European Research Council (CoG 724373)

Michael Sixt

Austrian Science Fund (FWF P29911)

Michael Sixt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments are in accordance with the Austrian law for animal experiments. Permission was granted by the Austrian Federal Ministry of Science, Research and Economy (identification code: BMWFW 66.018/0010-WF/V/3b/2016). Mice were bred and maintained at the local animal facility in accordance IST Austria Ethical Committee or purchased from Charles River and maintained at the local animal facility in accordance with IST Austria Ethical Committee.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.