EMBO molecular medicine · 2022
Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Kohl Lisa, Siddique Md Nur A Alam, Bodendorfer Barbara, Berger Raffaela, Preikschat Annica, Daniel Christoph, Ölke Martha, Liebler-Tenorio Elisabeth, Schulze-Luehrmann Jan, Mauermeir Michael, Yang Kai-Ting, Hayek Inaya, Szperlinski Manuela, Andrack Jennifer, Schleicher Ulrike, Bozec Aline, Krönke Gerhard, Murray Peter J, Wirtz Stefan, Yamamoto Masahiro, Schatz Valentin, Jantsch Jonathan, Oefner Peter, Degrandi Daniel, Pfeffer Klaus, Mertens-Scholz Katja, Rauber Simon, Bogdan Christian, Dettmer Katja, Lührmann Anja, Lang Roland
Аннотация
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.