Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice

Aurore Demars, Armelle Vitali, Audrey Comein, Elodie Carlier, Abdulkader Azouz, Stanislas Goriely, Justine Smout, Véronique Flamand, Mégane Van Gysel, Johan Wouters, Jan Abendroth, Thomas E Edwards, Arnaud Machelart, Eik Hoffmann, Priscille Brodin, Xavier De Bolle, Eric Muraille

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Abstract

Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, structural analysis suggests the binding of itaconate into the binding site of B. abortus isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ΔaceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ΔaceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.

Original languageEnglish
Article numbere1009887
Pages (from-to)e1009887
JournalPlos Pathogens
Volume17
Issue number9
DOIs
Publication statusPublished - Sep 2021

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