Article révisé par les pairs
Résumé : 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 Δ aceA B . abortus in vitro . Finally, we observed that, unlike the wt strain, the Δ aceA 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.

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