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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that ...a fraction of iPD patients may harbor a combination of common variants in nuclear‐encoded mitochondrial genes ultimately resulting in neurodegeneration.
Methods
We used mitochondria‐specific polygenic risk scores (mitoPRSs) and created pathway‐specific mitoPRSs using genotype data from different iPD case–control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE‐PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function.
Results
Common variants in genes regulating Oxidative Phosphorylation (OXPHOS‐PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.311.14–1.50, p‐value = 5.4e‐04; COURAGE‐PD OR = 1.231.18–1.27, p‐value = 1.5e‐29). Functional analyses in fibroblasts and induced pluripotent stem cells‐derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS‐PRS (p‐values < 0.05). Clinically, iPD patients with high OXPHOS‐PRS have a significantly earlier age at disease onset compared to low‐risk patients (false discovery rate FDR‐adj p‐value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS‐PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid.
Interpretation
OXPHOS‐PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133–149
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