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Modulation of the Mtor Pathway Plays a Central Role in Dendritic Cell bioRxiv preprint doi: https://doi.org/10.1101/2020.07.27.224055; this version posted July 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Research Paper 2 3 Modulation of the mTOR pathway plays a central role in dendritic cell 4 functions after Echinococcus granulosus antigen recognition. 5 6 Christian Rodriguez Rodrigues*1,2,3, María Celeste Nicolao2,3, Maia Chop1, Natalia Plá1, Mora 7 Massaro1,3, Julia Loos2,3, Andrea C. Cumino1,2,3. 8 9 1Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar 10 del Plata (UNMdP), Funes 3350, Nivel 2, (7600) Mar del Plata, Argentina. 11 2Instituto IPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del 12 Plata (UNMdP), Funes 3350, Nivel Cero, (7600) Mar del Plata, Argentina. 13 3Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. 14 15 16 * Corresponding author: 17 e-mail: [email protected] (C.R.R.) 18 19 20 21 22 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.27.224055; this version posted July 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 23 1. Abstract 24 Immune evasion is a hallmark of persistent echinococcal infection, comprising modulation of innate 25 immune cells and antigen-specific T cell responses. However, recognition of Echinococcus granulosus 26 by dendritic cells (DCs) is a key determinant of the host's response to this parasite. Given that mTOR 27 signaling pathway has been described as a regulator linking metabolism and immune function in DCs, 28 we reported for the first time in these cells, global translation levels, antigen uptake, phenotype, 29 cytokine transcriptional levels, and splenocyte priming activity upon recognition of the hydatid fluid 30 (HF) and the highly glycosylated laminar layer (LL). We found that LL induced a slight up-regulation 31 of CD86 and MHC II in DCs and also stimulated the production of IL-6 and TNF-. By contrast, HF 32 did not increase the expression of any co-stimulatory molecules, but also down-modulated CD40 and 33 stimulated the expression of the anti-inflammatory cytokine IL-10. Both parasitic antigens promoted 34 protein synthesis through mTOR activation. The use of rapamycin decreased the expression of the 35 cytokines tested, empowered the down-modulation of CD40 and also reduced splenocyte proliferation. 36 Finally, we showed that E. granulosus antigens increase the amounts of LC3-positive structures in 37 DCs which play critical roles in the presentation of these antigens to T cells. 38 39 Keywords: Echinococcus granulosus, purified laminar layer, hydatid fluid, immunomodulation, 40 mTOR, autophagy, tolerance, dendritic cells 41 42 2. Introduction 43 The cestode Echinococcus granulosus (Eg) is the etiological agent for cystic echinococcosis. This 44 parasite infects humans as an intermediate host in a zoonotic transmission cycle with worldwide 45 distribution 1,2. Cystic echinococcosis is considered as a re-emerging and neglected disease that 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.27.224055; this version posted July 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 46 causes serious chronic liver pathology, with a high fatality rate and poor prognosis without careful 47 clinical management. In the viscera of the intermediate host, the parasites develop fluid-filled cysts, 48 called hydatid cysts or metacestodes, that are isolated from the host by three layers. From inside to 49 outside, an internal germinal layer composed of totipotent cells, with a high metabolic rate and in 50 continuous cell division, that generates brood capsules and protoscoleces constituting the "hydatid 51 sand" 3. Furthermore, the parasite synthesizes the laminar layer (LL), an acellular structure rich in 52 mucins and polysaccharides that surrounds the metacestode, creating a mechanical and 53 immunological protective barrier, crucial in the Echinococcus–host interface 4,5. Externally, and as 54 a product of the host's response, an adventitial layer, composed of newly formed eosinophils, 55 fibroblasts, M2 macrophages, and capillaries, surrounds the LL. Under pressure and inside of the 56 cyst it is found the hydatid fluid (HF) constitute by different macromolecules including a wide 57 range of parasite and host proteins 6. During the infection course, the cyst may rupture or slowly 58 leak out, permeate into a coelomic cavity, open on an epithelial surface or empty into the lumen of 59 a hollow organ, leading to different host immune responses, ranging from a severe anaphylactic 60 shock to a spontaneous resolution of the infection 7. In this context, Eg-antigens of metacestodes 61 exposed and released in the tissues, lymphatics and circulation could be detected by dendritic cells 62 (DCs). 63 Dendritic cells as antigen-presenting cells play a key role in the immune homeostasis, but under 64 stress conditions rapidly respond to local or systemic perturbations by pathogenic or sterile insults 65 8. DCs capture antigens in the periphery or in the blood and migrate to the lymphoid organs, where 66 they activate the specific immune response by inducing cytokine release and presenting processed 67 peptides in a MHC molecule to specific T cells 9. This activation process, that includes cellular 68 shape changes, migration, expression of co-stimulatory molecules in the membrane, production of 69 cytokines, chemokines, lipid mediators, and antigen presentation must be metabolically supported 70 to be efficient. 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.27.224055; this version posted July 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 71 The mammalian target of rapamycin (mTOR) signaling pathway serves as a central regulator of 72 cell metabolism, growth, proliferation and survival. mTOR is a serine/threonine protein kinase that 73 forms the catalytic subunit of two distinct protein complexes, known as mTOR Complex 1 74 (mTORC1) and 2 (mTORC2) 10. These protein complexes sense growth factors, nutrients, and 75 energy cell status 11. While mTORC1 plays a key anabolic role in promoting cell growth and 76 proliferation, mTORC2 influences cell morphology through the regulation of cytoskeletal 77 organization 12. Activation of the phosphatidylinositol 3-kinase (PI3K)– protein kinase B (AKT)– 78 mTORC1 pathway is required for the in vivo development of normal numbers of mouse DCs in 79 the presence of Flt3L 13. In recent years, the reports that link the immunological pathways of 80 microbial sensing through different pattern recognition receptors to mTOR-dependent metabolic 81 pathways have increased 14–17. In fact, the bacterial lipopolysaccharide improved global protein 82 synthesis via TLR4-activation in human monocyte-derived DCs 18. Additionally, treatment of 83 human and mouse DCs or monocytes with rapamycin enhanced their production of IL‑12p40 and 84 IL‑12p70 and strongly reduced the expression of the anti-inflammatory cytokine IL‑10 after 85 stimulation with TLR ligands 13,19–25. Moreover, inhibition of mTOR abolished the ability to induce 86 IFN- and pro-inflammatory cytokine production by plasmacytoid dendritic cells 26,27, and 87 promoted in DCs the expression of the co-stimulatory molecule CD86, whereas PD-L1, a negative 88 regulator for T cell activation, is decreased 19,22,25,28. In addition, C-type lectin receptors recognized 89 complex glycan structures in pathogens and modulated the immune cell functions by mechanisms 90 dependent on the activation of mTOR 29. Rapamycin was also described to augments autophagy, 91 which is important for the presentation of endogenous and exogenous proteins on MHC class I and 92 class II molecules, thereby promoting activation of CD8+ and CD4+ T-cells respectively 30. On the 93 other hand, mTOR modulation is also a target by pathogens to improve their survival. In 94 Leishmania the protease GP63 cleaves mTOR on macrophages, inhibiting the mTORC1 with the 95 concomitant activation of the translational repressor 4E-BP1 and consequently promoting parasite 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.27.224055; this version posted July 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 96 proliferation 31. It has been reported that upon infection with Toxoplasma gondii, PI3K/Akt/mTOR 97 pathway is activated in macrophages, and this activation is required to avoid host cell defense 32. 98 In helminths, Brugia malayi inhibits the phosphorylation of mTOR and its downstream proteins 99 promoting autophagy 33 The hookworm Nippostrongylus brasiliensis modulates mTOR pathway 100 in macrophages to induce differentiation and functional abilities of M2 profile and Schistosoma 101 mansoni-soluble egg antigens via mTOR-dependent and -independent pathway condition human 102 DCs to skew immune responses towards Th2 response 34,35. 103 Recently, the modulation of these metabolic pathways by the parasite E. granulosus has been 104 reported. Eg excretory/secretory products activate the PI3K/AKT/mTOR pathway and the 105 recruitment of alternatively activated macrophages 36.
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