Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever

• Published in: bioRxiv
• Main Authors: Kohl, Lisa, Alam Siddique, Nur A, Bodendorfer, Barbara, Berger, Raffaela, Preikschat, Annica, Daniel, Christoph, Oelke, Martha, Mauermeir, Michael, Kai-Ting, Yang, Hayek, Inaya, Szperlinski, Mauela, Schulze-Luehrmann, Jan, Schleicher, Ulrike, Bozec, Aline, Kroenke, Gerhard, Murray, Peter J, Yamamoto, Masahiro, Schatz, Valentin, Jantsch, Joonathan, Oefner, Peter, Degrandi, Daniel, Pfeffer, Klaus, Rauber, Simon, Bogdan, Christian, Dettmer, Katja, Luhrmann, Anja, Lang, Roland
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.05.2022; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Aconitate decarboxylase; Chronic infection; Gene expression; Germfree; Immunology; Infections; Inflammation; Macrophages; Pathogens; Q fever; Replication; Trachea; itaconate; Q fever; immunometabolism; Immune responsive gene 1 (Irg1); Cis-aconitate decarboxylase 1 (Acod1)
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2022.05.10.491306

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.