Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death

Acinetobacter baumannii is a highly pathogenic Gram-negative bacterium that causes severe infections with very high fatality rates. A. baumannii infection triggers innate as well as adaptive immunity, however, our understanding of the inflammatory factors secreted by A. baumannii that alarm the immu...

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Main Authors: Varnesh Tiku, Chun Kew, Eric M. Kofoed, Yutian Peng, Ivan Dikic, Man-Wah Tan
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-05-01
Series:Frontiers in Microbiology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fmicb.2022.870101/full
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author Varnesh Tiku
Chun Kew
Chun Kew
Eric M. Kofoed
Yutian Peng
Ivan Dikic
Ivan Dikic
Ivan Dikic
Man-Wah Tan
author_facet Varnesh Tiku
Chun Kew
Chun Kew
Eric M. Kofoed
Yutian Peng
Ivan Dikic
Ivan Dikic
Ivan Dikic
Man-Wah Tan
author_sort Varnesh Tiku
collection DOAJ
description Acinetobacter baumannii is a highly pathogenic Gram-negative bacterium that causes severe infections with very high fatality rates. A. baumannii infection triggers innate as well as adaptive immunity, however, our understanding of the inflammatory factors secreted by A. baumannii that alarm the immune system remains limited. In this study, we report that the lab adapted and clinical strains of A. baumannii secrete an inflammatory bioactive factor which activates TLR2, leading to canonical IRAK4-dependent NF-κB signaling and production of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and activation of the inflammasome pathway causing pyroptotic cell death. Biochemical fractionation of the A. baumannii culture filtrate revealed the hydrophobic nature of the inflammatory factor. Concordantly, lipase treatment of the culture filtrate or TLR2 inhibition in macrophages abrogated NF-κB activation and cell death induction. Culture filtrates from the LPS- and lipoprotein-deficient A. baumannii mutants retain immuno-stimulatory properties suggesting that a lipid other than these known stimulatory molecules can trigger inflammation during A. baumannii infection. Our results reveal that A. baumannii secretes a previously unappreciated inflammatory bioactive lipid that activates multiple pro-inflammatory signaling pathways and induces cell death in human and murine macrophages.
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spelling doaj.art-698410c372334f9fab9cdca011bb54152022-12-22T02:53:31ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-05-011310.3389/fmicb.2022.870101870101Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell DeathVarnesh Tiku0Chun Kew1Chun Kew2Eric M. Kofoed3Yutian Peng4Ivan Dikic5Ivan Dikic6Ivan Dikic7Man-Wah Tan8Department of Infectious Diseases, Genentech, South San Francisco, CA, United StatesFaculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, GermanyDepartment of Infectious Diseases, Genentech, South San Francisco, CA, United StatesDepartment of Infectious Diseases, Genentech, South San Francisco, CA, United StatesFaculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt, GermanyBuchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, GermanyMax Planck Institute of Biophysics, Frankfurt, GermanyDepartment of Infectious Diseases, Genentech, South San Francisco, CA, United StatesAcinetobacter baumannii is a highly pathogenic Gram-negative bacterium that causes severe infections with very high fatality rates. A. baumannii infection triggers innate as well as adaptive immunity, however, our understanding of the inflammatory factors secreted by A. baumannii that alarm the immune system remains limited. In this study, we report that the lab adapted and clinical strains of A. baumannii secrete an inflammatory bioactive factor which activates TLR2, leading to canonical IRAK4-dependent NF-κB signaling and production of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and activation of the inflammasome pathway causing pyroptotic cell death. Biochemical fractionation of the A. baumannii culture filtrate revealed the hydrophobic nature of the inflammatory factor. Concordantly, lipase treatment of the culture filtrate or TLR2 inhibition in macrophages abrogated NF-κB activation and cell death induction. Culture filtrates from the LPS- and lipoprotein-deficient A. baumannii mutants retain immuno-stimulatory properties suggesting that a lipid other than these known stimulatory molecules can trigger inflammation during A. baumannii infection. Our results reveal that A. baumannii secretes a previously unappreciated inflammatory bioactive lipid that activates multiple pro-inflammatory signaling pathways and induces cell death in human and murine macrophages.https://www.frontiersin.org/articles/10.3389/fmicb.2022.870101/fullAcinetobacter baumanniivirulencecell deathinflammatory signalinginflammasomeNF-κB activation
spellingShingle Varnesh Tiku
Chun Kew
Chun Kew
Eric M. Kofoed
Yutian Peng
Ivan Dikic
Ivan Dikic
Ivan Dikic
Man-Wah Tan
Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death
Frontiers in Microbiology
Acinetobacter baumannii
virulence
cell death
inflammatory signaling
inflammasome
NF-κB activation
title Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death
title_full Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death
title_fullStr Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death
title_full_unstemmed Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death
title_short Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death
title_sort acinetobacter baumannii secretes a bioactive lipid that triggers inflammatory signaling and cell death
topic Acinetobacter baumannii
virulence
cell death
inflammatory signaling
inflammasome
NF-κB activation
url https://www.frontiersin.org/articles/10.3389/fmicb.2022.870101/full
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