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 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, significant 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.
Competing Interest Statement
The authors have declared no competing interest.
Subject Area
- Biochemistry (11571)
- Bioengineering (8622)
- Bioinformatics (28868)
- Biophysics (14803)
- Cancer Biology (11941)
- Cell Biology (17168)
- Clinical Trials (138)
- Developmental Biology (9302)
- Ecology (14019)
- Epidemiology (2067)
- Evolutionary Biology (18128)
- Genetics (12145)
- Genomics (16616)
- Immunology (11707)
- Microbiology (27692)
- Molecular Biology (11387)
- Neuroscience (60096)
- Paleontology (447)
- Pathology (1847)
- Pharmacology and Toxicology (3184)
- Physiology (4878)
- Plant Biology (10278)
- Synthetic Biology (2849)
- Systems Biology (7289)
- Zoology (1619)