RT Journal Article
SR Electronic
T1 Macrophages inhibit <em>Coxiella burnetii</em> by the ACOD1-itaconate pathway for containment of Q fever
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.10.491306
DO 10.1101/2022.05.10.491306
A1 Lisa Kohl
A1 Md. Nur A Alam Siddique
A1 Barbara Bodendorfer
A1 Raffaela Berger
A1 Annica Preikschat
A1 Christoph Daniel
A1 Martha Ölke
A1 Michael Mauermeir
A1 Kai-Ting Yang
A1 Inaya Hayek
A1 Manuela Szperlinski
A1 Jan Schulze-Luehrmann
A1 Ulrike Schleicher
A1 Aline Bozec
A1 Gerhard Krönke
A1 Peter J. Murray
A1 Stefan Wirtz
A1 Masahiro Yamamoto
A1 Valentin Schatz
A1 Jonathan Jantsch
A1 Peter Oefner
A1 Daniel Degrandi
A1 Klaus Pfeffer
A1 Simon Rauber
A1 Christian Bogdan
A1 Katja Dettmer
A1 Anja Lührmann
A1 Roland Lang
YR 2022
UL http://biorxiv.org/content/early/2022/05/11/2022.05.10.491306.abstract
AB 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 StatementThe authors have declared no competing interest.