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.

TNF and type I IFN induction of the IRG1-itaconate pathway restrictsCoxiella burnetiireplication within mouse macrophages

“…Furthermore, ITA potently restricted C. burnetii axenic growth, indicating a direct inhibitory effect by ITA on C. burnetii. Our findings with IRG1 and ITA restricting C. burnetii replication within murine macrophages are in agreement with recent findings by another group (68). They found that C. burnetii infection induced IRG1 expression in a MyD88-dependent manner, and that IRG1 and ITA restrict C. burnetii replication within murine macrophages.…”

“…Our data indicate that TNF is the likely candidate cytokine produced downstream of TLR/MyD88 signaling that drives IRG1 expression. Furthermore, they also found that Irg1 -/mice have a defect in control of C. burnetii infection in vivo and treatment of Irg1 -/mice with ITA reduced C. burnetii bacterial loads (68). Interestingly, they found that human macrophages produce much less itaconate than murine macrophages, which may explain why human macrophages are much more permissive for C. burnetii replication than murine macrophages (68).…”