Metabolic control of Brucella infection
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Brucella melitensis is a bacterial pathogen that constitutes a substantial threat to human and animal health. Here we unraveled the host-pathogen interplay in brucellosis providing insights into MyD88 signaling, metabolic dynamics, and the impact of vaccination. We show that MyD88 promotes macrophage glycolysis in response to B. melitensis infection. Its deficiency results in an increased availability of glucose in vivo, which Brucella can exploit via its glucose transporter, gluP. Additionally, we found that itaconate has antibacterial effects and regulates the production of IL1-[beta]. Metabolic profiling of murine spleens, livers, and reproductive tracts post-infection reveals tissue-specific changes linked to glutaminolysis. Vaccination-induced metabolic shifts promote a significant impact on the host's metabolite profile protecting in part by restricting glucose availability in an antibody-dependent manner. The gluP gene emerges as a crucial player in virulence, exhibiting distinct roles in vaccinated and naive hosts. Moreover, we suggest that other different virulence strategies are employed by B. melitensis in vaccinated versus naive hosts. In a pioneering approach, we used Tn-seq to study fitness of B. melitensis mutants in the context of vaccination. Mutants associated with maltose, myo-inositol, and niacin utilization are suggested to be involved in this fitness. The generation of a double knockout mutant sheds light on the specific role of BMEII0940-BMEII0941 genes in B. melitensis virulence. The findings contribute to a deeper understanding of the host-pathogen relationship in brucellosis, offering potential avenues for therapeutic interventions and vaccine development.
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Ph. D.