Modulation of the mTOR pathway plays a central role in dendritic cell functions after Echinococcus granulosus antigen recognition

Abstract

Immune evasion is a hallmark of persistent echinococcal infection, comprising modulation of innate immune cells and antigen-specific T cell responses. However, recognition of Echinococcus granulosus by dendritic cells (DCs) is a key determinant of the host's response to this parasite. Given that mTOR signaling pathway has been described as a regulator linking metabolism and immune function in DCs, we reported for the first time in these cells, global translation levels, antigen uptake, phenotype, cytokine transcriptional levels, and splenocyte priming activity upon recognition of the hydatid fluid (HF) and the highly glycosylated laminar layer (LL). We found that LL induced a slight up-regulation of CD86 and MHC II in DCs and also stimulated the production of IL-6 and TNF-α. By contrast, HF did not increase the expression of any co-stimulatory molecules, but also down-modulated CD40 and stimulated the expression of the anti-inflammatory cytokine IL-10. Both parasitic antigens promoted protein synthesis through mTOR activation. The use of rapamycin decreased the expression of the cytokines tested, empowered the down-modulation of CD40 and also reduced splenocyte proliferation. Finally, we showed that E. granulosus antigens increase the amounts of LC3-positive structures in DCs which play critical roles in the presentation of these antigens to T cells.

Substance P promotes immunotherapy efficacy for airway allergy

“…The weak signaling of mTOR linking to the JAK-STAT pathway implicate the expression of IL-10 is impaired. 23 The MAPK pathway also mapped to Mtor , as well as Ccr7 and Myd88 ( Fig. 4 B).…”

Hydatid fluid from Echinococcus granulosus induces autophagy in dendritic cells and promotes polyfunctional T-cell responses

“…T cell responses in Echinococcus infection are characterized by early T helper 1 (Th1)-polarized cytokine production, which tries to eliminate the parasite at the initial stages of development and shifts to a predominant Th2 cytokine response in the later chronic stage (Vuitton, 2003). As previously described, HF induced ambiguous IL-6 and IL-10 production in BMDCs and promoted splenocytes proliferation (Rodriguez Rodrigues et al, 2021). Patients with chronic cystic echinococossis generate Th1/Th2 responses accompanied by an increased number of regulatory T cells (Baz et al, 2006).…”

“…Interestingly, it has been observed that HF stimulation plus rapamycin treatment, BMDCs showed an additive effect. This observation was clearly detected in lysosomal acidification, the induction of autophagic gene transcription and the accumulation of LC3 + compartments (Rodriguez Rodrigues et al, 2021). The reason behind this stricking effect could be that while rapamycin inhibits mTOR, HF does not; it does not even induce it, but can directly enhance autophagy pathway via activation of the Beclin-1 complex.…”

“…In contrast, HF-differentiated DCs stimulated with lipopolysaccharide (LPS) showed weaker expression of costimulatory molecules and reduced production of IL-12 and TNF-α ( Riganò et al., 2007 ). We previously observed that HF-stimulated bone marrow derived dendritic cells (BMDCs) induced a slight phenotype maturation with down-modulation of CD40 and unconventional cytokine transcription with IL-6 and IL-10 production ( Rodriguez Rodrigues et al., 2021 ).…”

Effect and Mechanism of Harmine on Echinococcosis Based on Network Pharmacology

“…[23][24][25] Besides, IL-6 and TNF are related to the immune evasion of echinococcus infection. 26 Moreover, F3 is closely related to inflammatory bowel disease. 27 These conclusions indicate that our prediction results have a certain significance.…”