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Extracellular vesicles from Trypanosoma cruzi-dendritic cell interaction show modulatory properties and confer resistance to lethal infection as a cell-free based therapy strategy

ABSTRACT: Extracellular vesicles (EVs) include a heterogeneous group of particles. Microvesicles and exosomes are the most characterised vesicles. They can be distinguished by their size, morphology, origin and molecular composition. To date, increasing studies demonstrate that EVs mediates intercellular communication. EVs reach considerable interest in the scientific community due to their role in diverse processes including antigen-presentation, stimulation of anti-tumoral immune responses, tolerogenic or inflammatory effects. In pathogens, EVs shedding is well described in fungus, bacteria, protozoan parasites and helminths. For Trypanosoma cruzi EVs liberation and protein composition was previously described. Dendritic cells (DCs) are key players promoting the immune response against pathogens and also maintaining self-tolerance. In previous reports we have demonstrate that T. cruzi downregulates DCs immunogenicity in vitro and in vivo. Here we analyze EVs from the in vitro interaction between blood circulating tripomastigotes (Tp) and bone-marrow-derived DCs. We found that Tp incremented the number and the size of EVs in cultures with DCs. EVs displayed some exosome markers and intracellular RNA. Protein analysis demonstrated that the parasite changes the protein-EV profile of DCs. We observed that EVs from the interaction of Tp-DCs were easily captured by unstimulated-DCs in comparison with EVs from DCs cultured without the parasite, and also modify the activation status of LPS-stimulated DCs. Noteworthy, we found protection in animal treated with EVs DCs+Tp and challenged with T. cruzi lethal infection. Our goal is to go deep into the molecular characterization of EVs from the DCs-Tp interaction, in order to identify mediators for therapeutic purposes.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Trypanosoma Cruzi

TISSUE(S): Dendritic Cell

SUBMITTER: Luz Valero

LAB HEAD: Carolina V. Poncini

PROVIDER: PXD037795 | Pride | 2022-11-09

REPOSITORIES: Pride

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Project description:The female reproductive tract provides a unique environment for a successful pregnancy. It is imperative that the non-pregnant uterus be transformed into a capable environment for the establishment and maintenance of pregnancy. To achieve this, intimate cross-communication between the endometrium and the embryo is necessary at an early stage of life (Almiñana et al., 2012) a dialog which further influences subsequent fetal developmental potential (Fleming et al., 2004) and even post-natal performance. Initially, the trophoblast-derived estrogen is one of the most important embryonic signals to activate the maternal uterus for attachment (Pope & First 1985). Once the conceptus has established its position in the uterus (>d15), its development and growth also require many other maternal-embryonic cellular and molecular interactions to ensure substantial vascular changes in the endometrium and the chorioallantois, mainly development of capillaries under the lamina propriae, essential to provide full function to the pig epiteliochorial placenta required for a successful pregnancy. It is during the peri-attachment window between days 12-30 of gestation when most (20-30%) of the embryos produced in pig natural or artificial breeding die (reviewed by Edwards et al., 2012); embryonic death with a substantial impact on pig production efficiency, especially because it significantly limits litter size. Different studies have focused on the elucidation of the complex embryo-maternal communication network to reduce pregnancy loss. Among these, several studies examined gene expression during the peri-implantation stage, when the majority of embryonic losses occur, or have compared the transcriptomic profiles of pregnant and non- pregnant animals. Interestingly, these studies identified changes in the expression of genes that can -directly or indirectly- contribute to reproductive success such genes related to cell proliferation, hormone synthesis and metabolism, cell adhesion or those related to cytokine production and immune local response (Almiñana et al., 2012, Lin et al, 2015; Smolinska et al., 2019; Yang et al., 2020, Martinez et al., 2020, 2022). However, we should not forget that changes in gene expression do not always lead to a corresponding alteration in the expression of proteins, which are crucial components in all biological processes. The knowledge of the proteome is therefore equally relevant to gene expression changes, being able to help detecting both normal and abnormal physiological conditions. Proteome characterization can led to a better understanding of physiological processes and to identify proteins that may serve as potential biomarkers. To date, only a limited number of studies have unfortunately explored the protein expression profiles of the pig endometrium during the crucial period of maternal recognition of pregnancy, which occurs between day 9 and 13 (Jalali et al., 2015; Kaiser et al., 2006) or during mid/last-gestation, from 40 to 93 days of pregnancy (Chae et al., 2011; Wang et al., 2019). These studies have identified several proteins associated with endometrial function, which could play a role in maternal recognition and progression of pregnancy. Therefore, in order to fully understand the molecular interaction between the conceptus and its chorion with the endometrium, we have aimed to characterize the proteome profile of both, the non-pregnant (control) endometrium compared with that of the “pregnant”endometrium with present extraembryonic membranes between the 3rd and the 4th week period, when the major conceptus loss occurs.

Project description:Currently, micro RNAs (miRNAs) constitute a promising models for cell-to-cell communication since they are transferred between cells to execute essential roles in many processes. Their structure and size, in addition to various transport mechanisms, allow them to remain stable within various biological fluids, surviving in extremely adverse conditions, including low pH, boiling, and freezing. The presence of miRNAs in reproductive fluids, such as follicular, uterine and seminal fluid, indicate potential roles in the reproductive system. These extracellular miRNAs can be transported by lipoproteins (both HDL and LDL) or other proteins, including Argonaute2 (AGO2) and nucleophosmin1 (NPM1). Another transport system is mediated by extracellular vesicles (EVs), such as apoptotic bodies, microvesicles (MVs) and/or exosome-like vesicles. EVs protect miRNAs from degradation and contribute to their stability within biological fluids. Furthermore, EVs can transport a wide range of components packaged in a selective way. For instance, Squadrito et al. (2014), used macrophages and endothelial cells to demonstrate that the sorting of miRNAs into EVs for heterotrophic cell communication is altered by both, the presence of target transcripts and the self-presence of the respectively miRNA. In addition, the signature of miRNAs found in the exosomes significantly differed for those detected in the parent cells. To date, mechanisms controlling the specific loading of miRNAs into exosomes remain unclear. Indeed, several mechanisms may govern exosome sorting of specific subsets of miRNAs. MiRNA sorting appears to be influenced by different pathways and molecules in different cell types and tissues, and miRNAs contain well defined motifs (i.e., EXOmotifs), that direct the miRNA allocation into exosomes before delivery into recipient cells. A recent study showed that this RNA sequence can be recognized by the sumoylated form of the heterogeneous ribonucleoprotein A2B1 (hnRNPA2B1). Moreover, a terminal 30 nucleotide addition in miRNAs affects their selective sorting in B cells. Another hypothesis suggests that RNAs are selectively sorted depending on the differential affinity of RNA motifs towards the raft-like region of the cytoplasmic surface of microvesicular body (MVB) limiting membranes. Current data indicate that cells can communicate with each other through the transfer of miRNA-loaded exosomes. For example, monocyte-derived exosomes deliver miR-150 to endothelial cells and enhance endothelial cell migration by reducing c-myb expression. The miRNA content of exosomes plays a critical role in such cell-to-cell communication and determines the fate of recipient cells. Thus, exosomes derived from the bone marrow mesenchymal stromal cells of myeloma patients promote tumor growth depending on the content of miR-15a in exosomes. Our group has described a novel cell-to-cell communication mechanism involving the delivery of endometrial miRNAs from the maternal endometrium to the trophectoderm cells of preimplantation embryos. Specifically, in B6C3 derived mouse embryos, we found EV-associated and free miR-30d to cause overexpression of genes involved in embryonic adhesion processes, including Itb3, Itga7 and Cdh5. Furthermore, supplementing murine embryos with miR-30d significantly improved embryo adhesion, suggesting that external miRNAs may have a functional role as transcriptomic modifiers of preimplantation embryos. Based on profiling of miRNAs in endometrial fluid, maternally-derived miRNAs are present within EVs in the uterine microenvironment. The internalization of maternally-derived exosomes has been visualized, but the mechanism by which miR-30d becomes incorporated into exosomes remains unknown. The present study aimed to elucidate the underlying mechanism of hsa-miR-30d transfer from human endometrial epithelial cells (hEECs) to the interior of exosomes and eventually to early-stage blastocysts, using a mir-30d knockout murine mode.

			Action	DRS
	MC_160120_CD.wiff	Wiff
	MC_160120_CD.wiff.scan	Wiff
	MC_160120_CDTp.wiff	Wiff
	MC_160120_CDTp.wiff.scan	Wiff
	MC_160120_CDTp_NCBI.mgf	Mgf

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Extracellular vesicles from Trypanosoma cruzi-dendritic cell interaction show modulatory properties and confer resistance to lethal infection as a cell-free based therapy strategy

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