Project Details
Projekt
Macrophage control of Coxiella burnetii through itaconate: mechanism of transport, uptake and anti-microbial action
Subject Area
Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
Immunology
Immunology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 566461781
Q fever is caused by Coxiella (C.) burnetii and can become chronic with destructive inflammation in the vascular system. There is an urgent need for improved therapeutic approaches as even prolonged antibiotic treatment has limited efficacy. We recently showed that TLR-MyD88 sensing induces expression of the enzyme ACOD1 in infected macrophages and that its product itaconate restricts bacterial replication. Treatment with exogenous itaconate restored inhibition of C. burnetii replication in ACOD1-deficient macrophages and in mice, suggesting therapeutic potential. The present project proposal will investigate the mechanisms underlying the protective effect of the ACOD1-itaconate pathway in C. burnetii infection. Our first aim is to identify the molecular basis of regulated uptake and intracellular transport of itaconate in infected macrophages by testing the function of members of the SLC gene family. Next, we will address how itaconate alters anti-microbial capacities of macrophages and its impact on the intracellular trafficking and the biogenesis of the C. burnetii containing vacuole. Finally, to dissect how itaconate directly inhibits growth and survival of the bacteria its effects on the bacterial transcriptome and on specific metabolic pathways will be analyzed. Beyond elucidating host-mediated and direct antimicrobial effects of ITA during Q fever, we expect that the results obtained will be relevant for infections with other intracellular pathogens. Finally, mechanisms of uptake and transport of ITA identified here will be valuable for the expanding field of immunometabolism.
DFG Programme
Research Grants
