Extracellular Vesicles Derived From Trichinella spiralis Muscle Larvae Ameliorate TNBS-Induced Colitis in Mice

Abstract

Helminths are masters at modulating the host immune response through a wide variety of versatile mechanisms. These complex strategies facilitate parasite survival in the host and can also be exploited to prevent chronic immune disorders by minimizing excessive inflammation. Extracellular vesicles (EVs) are small membrane-bound structures secreted by helminths which mediate immune evasion during parasite infection. The goal of this study was to investigate the immunoregulatory properties of Trichinella spiralis EVs (Ts-EVs) in a murine model of colitis. We found that Ts-EVs significantly ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Ts-EVs alleviated intestinal epithelium barrier damage, markedly reduced pro-inflammatory cytokine secretion and neutrophil infiltration, and upregulated immunoregulatory cytokine expression in colon tissue. Ts-EVs also modulated the adaptive immune response by influencing T-cell composition. The numbers of Th1 and Th17 cells in MLNs, as well as the expression levels of Th1/Th17-associated cytokines and transcription factors in colon were reduced. In contrast, Th2 and Treg cells were increased after Ts-EVs treatment. Furthermore, sequencing of EV-derived microRNAs (miRNAs) indicated that an array of miRNAs was involved in the regulation of the host immune response, including inflammation. These findings expand our knowledge of host-parasite interactions, and may help design novel and effective strategies to prevent parasite infections or to treat inflammatory diseases like IBD. Further studies are needed to identify the specific cargo molecules carried by Ts-EVs and to clarify their roles during T. spiralis infection.

Excretory/Secretory Products From Trichinella spiralis Adult Worms Attenuated DSS-Induced Colitis in Mice by Driving PD-1-Mediated M2 Macrophage Polarization

“…However, the AES are a complex pool of various molecules secreted or excreted by the worms, which are not safe as therapeutic reagents and also not feasible for large-scale production. It is necessary to identify the specific molecules in the ES products involved in immunomodulation (46). LC-MS/MS identified more than 280 protein components in T. spiralis AES with 4 proteins having potential regulatory functions that include cysteine protease inhibitor, serine protease, 53 kDa excretory/secretory antigen, and glutathione-S-transferase (47)(48)(49).…”

Protective Immunity Against Neospora Caninum Infection Induced by 14-3-3 Protein in Mice

“…Our previous research indicated that NEVs were enriched for secreted membrane-associated proteins, including 14-3-3, and the EVs modulated the in ammatory cytokine expression of BMDMs by triggering TLR2 and MAPK signalling pathways in vitro [8]. Increasing evidence has indicated that EVs are used by parasites to orchestrate bene cial changes in the host environment and to ensure successful infection or activate the innate immune response to control infection [25,26,27]. EVs and their cargo can participate in cell-to-cell communication via various functional biomolecules, including proteins, bioactive lipids, and RNA, which can alter recipient cell functions [28,29,30]; therefore, our previous study also selected NEVs as vaccine controls.…”

The Two Faces of Nematode Infection: Virulence and Immunomodulatory Molecules From Nematode Parasites of Mammals, Insects and Plants

“…Extracellular vesicles (EVs) released by parasitic nematodes during infection may provide a powerful strategy for the parasitic nematode to generate widespread effects on host cells ( Coakley et al, 2015 ). Of therapeutic promise, treatment with EVs from T. spiralis and N. brasiliensis suppressed colitis of mice and protection was associated with reduced proinflammatory cytokines and increased Th2 and Treg responses ( Eichenberger et al, 2018 ; Yang et al, 2020 ). In addition to containing lipids and proteins that may be immunomodulatory, EVs may also serve as cargos to deliver small RNAs to host cells, such as macrophages and intestinal cells, where they target and suppress host RNA.…”

“…In addition to containing lipids and proteins that may be immunomodulatory, EVs may also serve as cargos to deliver small RNAs to host cells, such as macrophages and intestinal cells, where they target and suppress host RNA. sRNAs have been identified in EVs generated by several parasitic nematodes, including T. spiralis , N. brasiliensis , Trichuris muris , and H. polygyrus , where they are predicted to target host immune gene networks ( Tritten et al, 2017 ; Eichenberger et al, 2018 ; Chow et al, 2019 ; Yang et al, 2020 ). For example, H. polygyrus EVs were able to suppress macrophage responses and IL-33 signaling, and contained miRNAs that specifically targeted host DUSP1 RNA, a regulator of MAPK signaling ( Buck et al, 2014 ; Coakley et al, 2017 ).…”