MyD88-Dependent Glucose Restriction and Itaconate Production Control Brucella Infection
| Autor: | Catherine A. Chambers, Jerod A. Skyberg, Carolyn A. Lacey, Bárbara Ponzilacqua-Silva, Alexis S. Dadelahi |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
030106 microbiology Immunology Inflammation Brucella Microbiology Brucellosis Proinflammatory cytokine Interferon-gamma Mice 03 medical and health sciences In vivo Brucella melitensis medicine Animals Macrophage Host Response and Inflammation biology Macrophages Intracellular parasite Glucose transporter Succinates biology.organism_classification In vitro Mice Inbred C57BL Glucose 030104 developmental biology Infectious Diseases Myeloid Differentiation Factor 88 Cytokines Parasitology medicine.symptom Glycolysis Signal Transduction |
| Zdroj: | Infect Immun |
| ISSN: | 1098-5522 0019-9567 |
| Popis: | Brucellosis is one of the most common global zoonoses and is caused by facultative intracellular bacteria of the genus Brucella. Numerous studies have found that MyD88 signaling contributes to protection against Brucella; however, the underlying mechanism has not been entirely defined. Here, we show that MyD88 signaling in hematopoietic cells contributes both to inflammation and to control of Brucella melitensis infection in vivo. While the protective role of MyD88 in Brucella infection has often been attributed to promotion of gamma interferon (IFN-γ) production, we found that MyD88 signaling restricts host colonization by B. melitensis even in the absence of IFN-γ. In vitro, we show that MyD88 promotes macrophage glycolysis in response to B. melitensis. Interestingly, a B. melitensis mutant lacking the glucose transporter, GluP, was more highly attenuated in MyD88(−/−) than in wild-type mice, suggesting MyD88 deficiency results in an increased availability of glucose in vivo, which Brucella can exploit via GluP. Metabolite profiling of macrophages identified several metabolites regulated by MyD88 in response to B. melitensis, including itaconate. Subsequently, we found that itaconate has antibacterial effects against Brucella and also regulates the production of proinflammatory cytokines in B. melitensis-infected macrophages. Mice lacking the ability to produce itaconate were also more susceptible to B. melitensis in vivo. Collectively, our findings indicate that MyD88-dependent changes in host metabolism contribute to control of Brucella infection. |
| Databáze: | OpenAIRE |
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