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

Kohl, L.; Siddique, N. A. A.; Bodendorfer, B.; Berger, R.; Preikschat, A.; Daniel, C.; Oelke, M.; Mauermeir, M.; Yang, K.-T.; Hayek, I.; Szperlinski, M.; Schulze-Luehrmann, J.; Schleicher, U.; Bozec, A.; Kroenke, G.; Murray, P. J.; Yamamoto, M.; Schatz, V.; Jantsch, J.; Oefner, P.; Degrandi, D.; Pfeffer, K.; Rauber, S.; Bogdan, C.; Dettmer, K.; Luhrmann, A.; Lang, R.

doi:10.1101/2022.05.10.491306

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bioRxiv · 10.1101/2022.05.10.491306

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

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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.

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Kohl, L., Siddique, N. A. A., Bodendorfer, B., Berger, R., Preikschat, A., Daniel, C., Oelke, M., Mauermeir, M., Yang, K.-T., Hayek, I., Szperlinski, M., Schulze-Luehrmann, J., Schleicher, U., Bozec, A., Kroenke, G., Murray, P. J., Yamamoto, M., Schatz, V., Jantsch, J., Oefner, P., Degrandi, D., Pfeffer, K., Rauber, S., Bogdan, C., Dettmer, K., Luhrmann, A., Lang, R.. 2022-05-11. Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever. https://doi.org/10.1101/2022.05.10.491306

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