Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever
Abstract Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis‐aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fe...
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Springer Nature
2022-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202215931 |
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| author | Lisa Kohl Md Nur A Alam Siddique Barbara Bodendorfer Raffaela Berger Annica Preikschat Christoph Daniel Martha Ölke Elisabeth Liebler‐Tenorio Jan Schulze‐Luehrmann Michael Mauermeir Kai‐Ting Yang Inaya Hayek Manuela Szperlinski Jennifer Andrack Ulrike Schleicher Aline Bozec Gerhard Krönke Peter J Murray Stefan Wirtz Masahiro Yamamoto Valentin Schatz Jonathan Jantsch Peter Oefner Daniel Degrandi Klaus Pfeffer Katja Mertens‐Scholz Simon Rauber Christian Bogdan Katja Dettmer Anja Lührmann Roland Lang |
| author_facet | Lisa Kohl Md Nur A Alam Siddique Barbara Bodendorfer Raffaela Berger Annica Preikschat Christoph Daniel Martha Ölke Elisabeth Liebler‐Tenorio Jan Schulze‐Luehrmann Michael Mauermeir Kai‐Ting Yang Inaya Hayek Manuela Szperlinski Jennifer Andrack Ulrike Schleicher Aline Bozec Gerhard Krönke Peter J Murray Stefan Wirtz Masahiro Yamamoto Valentin Schatz Jonathan Jantsch Peter Oefner Daniel Degrandi Klaus Pfeffer Katja Mertens‐Scholz Simon Rauber Christian Bogdan Katja Dettmer Anja Lührmann Roland Lang |
| author_sort | Lisa Kohl |
| collection | DOAJ |
| description | Abstract Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis‐aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti‐microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1‐derived itaconate is a key factor in the macrophage‐mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever. |
| format | Article |
| id | doaj-art-1b69987f304e4114b08d5e4633d04bb6 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-1b69987f304e4114b08d5e4633d04bb62025-08-24T11:43:42ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-12-0115212010.15252/emmm.202215931Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q feverLisa Kohl0Md Nur A Alam Siddique1Barbara Bodendorfer2Raffaela Berger3Annica Preikschat4Christoph Daniel5Martha Ölke6Elisabeth Liebler‐Tenorio7Jan Schulze‐Luehrmann8Michael Mauermeir9Kai‐Ting Yang10Inaya Hayek11Manuela Szperlinski12Jennifer Andrack13Ulrike Schleicher14Aline Bozec15Gerhard Krönke16Peter J Murray17Stefan Wirtz18Masahiro Yamamoto19Valentin Schatz20Jonathan Jantsch21Peter Oefner22Daniel Degrandi23Klaus Pfeffer24Katja Mertens‐Scholz25Simon Rauber26Christian Bogdan27Katja Dettmer28Anja Lührmann29Roland Lang30Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergInstitute of Functional Genomics, University of RegensburgMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergDepartment of Nephropathology, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergInstitute of Molecular Pathogenesis, Friedrich‐Loeffler‐Institut, Federal Research Institute for Animal HealthMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergDepartment of Medicine 3, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergInstitute of Bacterial Infections and Zoonoses, Friedrich‐Loeffler‐Institut, Federal Research Institute for Animal HealthMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergDepartment of Medicine 3, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergDepartment of Medicine 3, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergMax Planck Institute for BiochemistryDeutsches Zentrum für Immuntherapie (DZI), Friedrich‐Alexander‐Universität Erlangen‐Nürnberg and Universitätsklinikum ErlangenImmunology Frontier Research Center, Osaka UniversityInstitute of Clinical Microbiology, University Hospital RegensburgInstitute of Clinical Microbiology, University Hospital RegensburgInstitute of Functional Genomics, University of RegensburgInstitute of Medical Microbiology, Heinrich Heine University DüsseldorfInstitute of Medical Microbiology, Heinrich Heine University DüsseldorfInstitute of Bacterial Infections and Zoonoses, Friedrich‐Loeffler‐Institut, Federal Research Institute for Animal HealthDepartment of Medicine 3, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergInstitute of Functional Genomics, University of RegensburgMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergMikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergAbstract Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis‐aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti‐microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1‐derived itaconate is a key factor in the macrophage‐mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.https://doi.org/10.15252/emmm.202215931Cis‐aconitate decarboxylase 1Coxiella burnetiiImmune responsive gene 1immunometabolismitaconate |
| spellingShingle | Lisa Kohl Md Nur A Alam Siddique Barbara Bodendorfer Raffaela Berger Annica Preikschat Christoph Daniel Martha Ölke Elisabeth Liebler‐Tenorio Jan Schulze‐Luehrmann Michael Mauermeir Kai‐Ting Yang Inaya Hayek Manuela Szperlinski Jennifer Andrack Ulrike Schleicher Aline Bozec Gerhard Krönke Peter J Murray Stefan Wirtz Masahiro Yamamoto Valentin Schatz Jonathan Jantsch Peter Oefner Daniel Degrandi Klaus Pfeffer Katja Mertens‐Scholz Simon Rauber Christian Bogdan Katja Dettmer Anja Lührmann Roland Lang Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever EMBO Molecular Medicine Cis‐aconitate decarboxylase 1 Coxiella burnetii Immune responsive gene 1 immunometabolism itaconate |
| title | Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever |
| title_full | Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever |
| title_fullStr | Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever |
| title_full_unstemmed | Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever |
| title_short | Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever |
| title_sort | macrophages inhibit coxiella burnetii by the acod1 itaconate pathway for containment of q fever |
| topic | Cis‐aconitate decarboxylase 1 Coxiella burnetii Immune responsive gene 1 immunometabolism itaconate |
| url | https://doi.org/10.15252/emmm.202215931 |
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