The aryl hydrocarbon receptor and FOS mediate cytotoxicity induced by Acinetobacter baumannii

Chun Kew, Cristian Prieto-Garcia, Anshu Bhattacharya, Manuela Tietgen, Craig R. MacNair, Lindsey A. Carfrae, João Mello-Vieira, Stephan Klatt, Yi-Lin Cheng, Rajeshwari Rathore, Elise Gradhand, Ingrid Fleming, Man-Wah Tan, Stephan Göttig, Volkhard A. J. Kempf and Ivan Dikic ()
Additional contact information
Chun Kew: Goethe University
Cristian Prieto-Garcia: Goethe University
Anshu Bhattacharya: Goethe University
Manuela Tietgen: Hospital of the Goethe University
Craig R. MacNair: 1 DNA Way
Lindsey A. Carfrae: 1 DNA Way
João Mello-Vieira: Goethe University
Stephan Klatt: Goethe University
Yi-Lin Cheng: Goethe University
Rajeshwari Rathore: Goethe University
Elise Gradhand: Goethe University
Ingrid Fleming: Goethe University
Man-Wah Tan: 1 DNA Way
Stephan Göttig: Hospital of the Goethe University
Volkhard A. J. Kempf: Hospital of the Goethe University
Ivan Dikic: Goethe University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells.

Date: 2024
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DOI: 10.1038/s41467-024-52118-7

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