The aryl hydrocarbon receptor and FOS mediate cytotoxicity induced by Acinetobacter baumannii.
Receptors, Aryl Hydrocarbon
/ metabolism
Acinetobacter baumannii
/ metabolism
Humans
Animals
Mice
Acinetobacter Infections
/ microbiology
Kynurenine
/ metabolism
Proto-Oncogene Proteins c-fos
/ metabolism
Tryptophan
/ metabolism
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Host-Pathogen Interactions
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 Sep 2024
11 Sep 2024
Historique:
received:
07
03
2023
accepted:
27
08
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
11
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39261458
doi: 10.1038/s41467-024-52118-7
pii: 10.1038/s41467-024-52118-7
doi:
Substances chimiques
Receptors, Aryl Hydrocarbon
0
Kynurenine
343-65-7
Proto-Oncogene Proteins c-fos
0
Tryptophan
8DUH1N11BX
Basic Helix-Loop-Helix Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7939Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 259130777
Organisme : Fraunhofer-Gesellschaft (Fraunhofer Organization)
ID : TheraNova
Informations de copyright
© 2024. The Author(s).
Références
Tiku, V. Acinetobacter baumannii: virulence strategies and host defense mechanisms. DNA Cell Biol. 41, 43–48 (2022).
pubmed: 34941456
pmcid: 8787692
doi: 10.1089/dna.2021.0588
Wong, D. et al. Clinical and pathophysiological overview of acinetobacter infections: a century of challenges. Clin. Microbiol Rev. 30, 409–447 (2017).
pubmed: 27974412
doi: 10.1128/CMR.00058-16
Harding, C. M., Hennon, S. W. & Feldman, M. F. Uncovering the mechanisms of Acinetobacter baumannii virulence. Nat. Rev. Microbiol. 16, 91–102 (2018).
pubmed: 29249812
doi: 10.1038/nrmicro.2017.148
Göttig, S. et al. Detection of pan drug-resistant Acinetobacter baumannii in Germany. J. Antimicrob. Chemother. 69, 2578–2579 (2014).
pubmed: 24833751
doi: 10.1093/jac/dku170
Tillotson, G. A crucial list of pathogens. Lancet Infect. Dis. 18, 234–236 (2018).
pubmed: 29276050
doi: 10.1016/S1473-3099(17)30754-5
Zumla, A. et al. Host-directed therapies for infectious diseases: current status, recent progress, and future prospects. Lancet Infect. Dis. 16, e47–e63 (2016).
pubmed: 27036359
pmcid: 7164794
doi: 10.1016/S1473-3099(16)00078-5
Wallis, R. S., O’Garra, A., Sher, A. & Wack, A. Host-directed immunotherapy of viral and bacterial infections: past, present and future. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00734-z (2022).
Tobin, D. M. Host-directed therapies for tuberculosis: fig. 1. Cold Spring Harb. Perspect. Med 5, a021196 (2015).
pubmed: 25986592
pmcid: 4588138
doi: 10.1101/cshperspect.a021196
Zumla, A. et al. Towards host-directed therapies for tuberculosis. Nat. Rev. Drug Discov. 14, 511–512 (2015).
pubmed: 26184493
doi: 10.1038/nrd4696
O’Donoghue, E. J. & Krachler, A. M. Mechanisms of outer membrane vesicle entry into host cells. Cell Microbiol. 18, 1508–1517 (2016).
pubmed: 27529760
pmcid: 5091637
doi: 10.1111/cmi.12655
Nonaka, S., Kadowaki, T. & Nakanishi, H. Secreted gingipains from Porphyromonas gingivalis increase permeability in human cerebral microvascular endothelial cells through intracellular degradation of tight junction proteins. Neurochem. Int. 154, 105282 (2022).
pubmed: 35032577
doi: 10.1016/j.neuint.2022.105282
Seyama, M. et al. Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165731 (2020).
pubmed: 32088316
doi: 10.1016/j.bbadis.2020.165731
Farrugia, C., Stafford, G. P. & Murdoch, C. Porphyromonas gingivalis outer membrane vesicles increase vascular permeability. J. Dent. Res. 99, 1494–1501 (2020).
pubmed: 32726180
doi: 10.1177/0022034520943187
Bielaszewska, M. et al. Enterohemorrhagic Escherichia coli hemolysin employs outer membrane vesicles to target mitochondria and cause endothelial and epithelial apoptosis. PLoS Pathog. 9, e1003797 (2013).
pubmed: 24348251
pmcid: 3861543
doi: 10.1371/journal.ppat.1003797
Balsalobre, C. et al. Release of the type I secreted alpha-haemolysin via outer membrane vesicles from Escherichia coli. Mol. Microbiol. 59, 99–112 (2006).
pubmed: 16359321
doi: 10.1111/j.1365-2958.2005.04938.x
Tiku, V. et al. Outer membrane vesicles containing OmpA induce mitochondrial fragmentation to promote pathogenesis of Acinetobacter baumannii. Sci. Rep. 11, 618 (2021).
pubmed: 33436835
pmcid: 7804284
doi: 10.1038/s41598-020-79966-9
Hop, H. T. et al. The key role of c-Fos for immune regulation and bacterial dissemination in brucella infected macrophage. Front. Cell Infect. Microbiol. 8, 287 (2018).
pubmed: 30186773
pmcid: 6110913
doi: 10.3389/fcimb.2018.00287
Lee, Y.-N. et al. c-Fos as a regulator of degranulation and cytokine production in FcεRI-activated mast cells. J. Immunol. 173, 2571–2577 (2004).
pubmed: 15294973
doi: 10.4049/jimmunol.173.4.2571
Ray, N. et al. c-Fos suppresses systemic inflammatory response to endotoxin. Int. Immunol. 18, 671–677 (2006).
pubmed: 16569682
doi: 10.1093/intimm/dxl004
Liu, Y., Shepherd, E. G. & Nelin, L. D. MAPK phosphatases — regulating the immune response. Nat. Rev. Immunol. 7, 202–212 (2007).
pubmed: 17318231
doi: 10.1038/nri2035
Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019).
pubmed: 30718831
doi: 10.1038/s41577-019-0125-8
Bessede, A. et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511, 184–190 (2014).
pubmed: 24930766
pmcid: 4098076
doi: 10.1038/nature13323
Shinde, R. et al. Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. 19, 571–582 (2018).
pubmed: 29760532
pmcid: 5976527
doi: 10.1038/s41590-018-0107-1
Rubio, T. et al. Incidence of an intracellular multiplication niche among acinetobacter baumannii clinical isolates. mSystems 7, e0048821 (2022).
pubmed: 35103489
doi: 10.1128/msystems.00488-21
Weidensdorfer, M. et al. The Acinetobacter trimeric autotransporter adhesin Ata controls key virulence traits of Acinetobacter baumannii. Virulence 10, 68–81 (2019).
pubmed: 31874074
pmcid: 6363060
doi: 10.1080/21505594.2018.1558693
Tiku, V. et al. Acinetobacter baumannii Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death. Front. Microbiol. 13, 870101 (2022).
pubmed: 35615509
pmcid: 9125205
doi: 10.3389/fmicb.2022.870101
Aikawa, Y. et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat. Biotechnol. 26, 817–823 (2008).
pubmed: 18587386
doi: 10.1038/nbt1412
Ye, N., Ding, Y., Wild, C., Shen, Q. & Zhou, J. Small molecule inhibitors targeting activator protein 1 (AP-1). J. Med. Chem. 57, 6930–6948 (2014).
pubmed: 24831826
pmcid: 4148154
doi: 10.1021/jm5004733
Fanjul, A. et al. A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 372, 107–111 (1994).
pubmed: 7969403
doi: 10.1038/372107a0
The ENCODE Project Consortium. A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).
The ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) project. Science 306, 636–640 (2004).
Centers for Disease Control and Prevention. AR Bank # 0280 Acinetobacter baumannii. https://wwwn.cdc.gov/ARIsolateBank/Panel/IsolateDetail?IsolateID=280&PanelID=1 (2024).
Li, X. et al. Safety and immunogenicity of a new glycoengineered vaccine against Acinetobacter baumannii in mice. Microb. Biotechnol. 15, 703–716 (2022).
pubmed: 33755314
doi: 10.1111/1751-7915.13770
Harris, G., Holbein, B. E., Zhou, H., Xu, H. H. & Chen, W. Potential mechanisms of mucin-enhanced acinetobacter baumannii virulence in the mouse model of intraperitoneal infection. Infect. Immun. 87, e00591–19 (2019).
pubmed: 31405959
pmcid: 6803341
doi: 10.1128/IAI.00591-19
Harris, G., KuoLee, R., Xu, H. H. & Chen, W. Acute intraperitoneal infection with a hypervirulent Acinetobacter baumannii isolate in mice. Sci. Rep. 9, 6538 (2019).
pubmed: 31024025
pmcid: 6484084
doi: 10.1038/s41598-019-43000-4
Bomberger, J. M. et al. Long-distance delivery of bacterial virulence factors by pseudomonas aeruginosa outer membrane vesicles. PLoS Pathog. 5, e1000382 (2009).
pubmed: 19360133
pmcid: 2661024
doi: 10.1371/journal.ppat.1000382
Vanaja, S. K. et al. Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165, 1106–1119 (2016).
pubmed: 27156449
pmcid: 4874922
doi: 10.1016/j.cell.2016.04.015
Manning, A. J. & Kuehn, M. J. Contribution of bacterial outer membrane vesicles to innate bacterial defense. BMC Microbiol 11, 258 (2011).
pubmed: 22133164
pmcid: 3248377
doi: 10.1186/1471-2180-11-258
Ye, C. et al. Inappropriate use of antibiotics exacerbates inflammation through OMV-induced pyroptosis in MDR Klebsiella pneumoniae infection. Cell Rep. 36, 109750 (2021).
pubmed: 34551309
doi: 10.1016/j.celrep.2021.109750
Kosgodage, U. S. et al. Peptidylarginine deiminase inhibitors reduce bacterial membrane vesicle release and sensitize bacteria to antibiotic treatment. Front. Cell Infect. Microbiol. 9, 227 (2019).
pubmed: 31316918
pmcid: 6610471
doi: 10.3389/fcimb.2019.00227
Moon, D. C. et al. Acinetobacter baumannii outer membrane protein a modulates the biogenesis of outer membrane vesicles. J. Microbiol. 50, 155–160 (2012).
pubmed: 22367951
doi: 10.1007/s12275-012-1589-4
Izawa, T. et al. The nuclear receptor AhR controls bone homeostasis by regulating osteoclast differentiation via the RANK/c-Fos signaling axis. J. Immunol. 197, 4639–4650 (2016).
pubmed: 27849171
pmcid: 5133671
doi: 10.4049/jimmunol.1600822
Dong, F. & Perdew, G. H. The aryl hydrocarbon receptor as a mediator of host-microbiota interplay. Gut Microbes 12, 1859812 (2020).
pubmed: 33382356
pmcid: 7781536
doi: 10.1080/19490976.2020.1859812
MacLean-Fletcher, S. Mechanism of action of cytochalasin B on actin. Cell 20, 329–341 (1980).
pubmed: 6893016
doi: 10.1016/0092-8674(80)90619-4
Macia, E. et al. Dynasore, a cell-permeable inhibitor of dynamin. Dev. Cell 10, 839–850 (2006).
pubmed: 16740485
doi: 10.1016/j.devcel.2006.04.002
Bielaszewska, M. et al. Host cell interactions of outer membrane vesicle-associated virulence factors of enterohemorrhagic Escherichia coli O157: intracellular delivery, trafficking and mechanisms of cell injury. PLoS Pathog. 13, e1006159 (2017).
pubmed: 28158302
pmcid: 5310930
doi: 10.1371/journal.ppat.1006159
Ranf, S. Immune sensing of lipopolysaccharide in plants and animals: same but different. PLoS Pathog. 12, e1005596 (2016).
pubmed: 27281177
pmcid: 4900518
doi: 10.1371/journal.ppat.1005596
Simpson, B. W. et al. Acinetobacter baumannii can survive with an outer membrane lacking lipooligosaccharide due to structural support from elongasome peptidoglycan synthesis. mBio 12, e0309921 (2021).
pubmed: 34844428
doi: 10.1128/mBio.03099-21
Moffatt, J. H. et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob. Agents Chemother. 54, 4971–4977 (2010).
pubmed: 20855724
pmcid: 2981238
doi: 10.1128/AAC.00834-10
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).
pubmed: 25119034
doi: 10.1038/nature13683
Medvedev, A. E. & Vogel, S. N. Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance. J. Endotoxin Res 9, 60–64 (2003).
pubmed: 12691621
doi: 10.1177/09680519030090010801
Badawy, A. A.-B. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int. J. Tryptophan Res. 10, 117864691769193 (2017).
doi: 10.1177/1178646917691938
Nakabayashi, H., Taketa, K., Miyano, K., Yamane, T. & Sato, J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 42, 3858–3863 (1982).
pubmed: 6286115
Preston, G. A. et al. Induction of apoptosis by c-Fos protein. Mol. Cell Biol. 16, 211–218 (1996).
pubmed: 8524298
pmcid: 230994
doi: 10.1128/MCB.16.1.211
Meyer-ter-Vehn, T., Covacci, A., Kist, M. & Pahl, H. L. Helicobacter pylori activates mitogen-activated protein kinase cascades and induces expression of the proto-oncogenes c-fos and c-jun. J. Biol. Chem. 275, 16064–16072 (2000).
pubmed: 10747974
doi: 10.1074/jbc.M000959200
Jan, A. T. Outer Membrane Vesicles (OMVs) of gram-negative bacteria: a perspective update. Front. Microbiol. 8, 1053 (2017).
pubmed: 28649237
pmcid: 5465292
doi: 10.3389/fmicb.2017.01053
Gutiérrez-Vázquez, C. & Quintana, F. J. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48, 19–33 (2018).
pubmed: 29343438
pmcid: 5777317
doi: 10.1016/j.immuni.2017.12.012
Han, E. et al. Extracellular RNAs in periodontopathogenic outer membrane vesicles promote TNF‐α production in human macrophages and cross the blood‐brain barrier in mice. FASEB J. 33, 13412–13422 (2019).
pubmed: 31545910
pmcid: 6894046
doi: 10.1096/fj.201901575R
Gurczynski, S. J. et al. Stem cell transplantation uncovers TDO-AHR regulation of lung dendritic cells in herpesvirus-induced pathology. JCI Insight 6, e139965 (2021).
pubmed: 33491663
pmcid: 7934859
doi: 10.1172/jci.insight.139965
Li, S. et al. A comprehensive analysis of TDO2 expression in immune cells and characterization of immune cell phenotype in TDO2 knockout mice. Transgenic Res. 30, 781–797 (2021).
pubmed: 34529208
doi: 10.1007/s11248-021-00281-8
Torosyan, R. et al. Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway. Cell Rep. 36, 109547 (2021).
pubmed: 34407414
pmcid: 8487442
doi: 10.1016/j.celrep.2021.109547
Miller, C. L., Llenos, I. C., Dulay, J. R. & Weis, S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 1073–1074, 25–37 (2006).
pubmed: 16448631
doi: 10.1016/j.brainres.2005.12.056
Miller, C. L. et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis. 15, 618–629 (2004).
pubmed: 15056470
doi: 10.1016/j.nbd.2003.12.015
Jones, E. J. et al. The uptake, trafficking, and biodistribution of bacteroides thetaiotaomicron generated outer membrane vesicles. Front. Microbiol. 11, 57 (2020).
pubmed: 32117106
pmcid: 7015872
doi: 10.3389/fmicb.2020.00057
Jang, S. C. et al. In vivo kinetic biodistribution of nano-sized outer membrane vesicles derived from bacteria. Small 11, 456–461 (2015).
pubmed: 25196673
doi: 10.1002/smll.201401803
Opitz, C. A. et al. The therapeutic potential of targeting tryptophan catabolism in cancer. Br. J. Cancer 122, 30–44 (2020).
pubmed: 31819194
doi: 10.1038/s41416-019-0664-6
van de Velde, L.-A. et al. Stress kinase GCN2 controls the proliferative fitness and trafficking of cytotoxic T cells independent of environmental amino acid sensing. Cell Rep. 17, 2247–2258 (2016).
pubmed: 27880901
pmcid: 5131879
doi: 10.1016/j.celrep.2016.10.079
Orsini, H. et al. GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice. Brain Behav. Immun. 37, 177–186 (2014).
pubmed: 24362236
doi: 10.1016/j.bbi.2013.12.012
Keil, M. et al. General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation. J. Neuroimmunol. 297, 117–126 (2016).
pubmed: 27397084
doi: 10.1016/j.jneuroim.2016.05.014
Zamyatina, A. & Heine, H. Lipopolysaccharide recognition in the crossroads of TLR4 and caspase-4/11 mediated inflammatory pathways. Front. Immunol. 11, 585146 (2020).
pubmed: 33329561
pmcid: 7732686
doi: 10.3389/fimmu.2020.585146
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. (National Academies Press, 2011).
Ge, S. X., Jung, D. & Yao, R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics 36, 2628–2629 (2020).
pubmed: 31882993
doi: 10.1093/bioinformatics/btz931
Kakuda, S., Yahata, T. & Kaneko, M. Oral Composition Comprising 3-[5-[4-(cyclopentyloxy)−2-hydroxybenzoyl]−2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl]propionic Acid Or Salt Thereof. https://patents.google.com/patent/US8093289B2/en (2012).
Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543–D552 (2022).
pubmed: 34723319
doi: 10.1093/nar/gkab1038