Regulation of cDC1 functions by the UPR sensor IRE1 during Toxoplasma gondii infection – ImmunUP
Induction of the unfolded protein response (UPR) has emerged as a key regulatory mechanism that controls inflammatory processes, notably in response to infections. We recently demonstrated that induction of the UPR sensor IRE1 in dendritic cells (DC) infected by the intracellular parasite Toxoplasma gondii (Tg) promotes inflammatory cytokine production and MHC-I presentation of secreted parasite antigens. In addition, activation of IRE1 in splenic cDC1 stimulates T cell protective responses and is essential to control parasite dissemination. However, the mechanisms by which IRE1 regulates cDC1 functions remain to be elucidated. Besides its induction by TLR-mediated sensing of microbial compounds, IRE1 is also a key sensor of cellular lipid homeostasis. We observed that DC infected with the cyst-forming type II Tg strain display an increase in saturated FA and cholesterol content as well as lipid droplet formation, a process that seems to contribute to IRE1 activation. IRE1-induced pathways may in turn regulates lipid metabolism thereby promoting DC functions and altering parasite fitness. Using complementary in vitro and in vivo approaches, our project aims to address two key unresolved questions that emerged from our recent work: 1) how does IRE1 regulate immunogenic maturation of cDC1 triggered by the infection 2) how does IRE1 promote MHC-I presentation of parasite antigens, with a specific focus on lipid metabolism regulation. In the actual context of fast-growing microbial antibiotic resistance, therapies modulating the immune response via modulation of the UPR might open new valuable perspectives to fight infections. Moreover, finding new strategies to boost antigen presentation by DC is of importance to ameliorate vaccine efficacy.
Madame Sabrina Marion (Institut national de la sante et de la recherche medicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INFINITy Institut national de la sante et de la recherche medicale
Institut national de la sante et de la recherche medicale
VIB- Center for Inflammation Research
Help of the ANR 404,765 euros
Beginning and duration of the scientific project: January 2023 - 36 Months