Taenia solium cysticerci's extracellular vesicles Attenuate the AKT/mTORC1 pathway for Alleviating DSS-induced colitis in a murine model
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Murine Colitis Modeling using Dextran Sulfate Sodium DSS
Published on: January 19, 2010
Suraj Singh Rawat1, Anand Kumar Keshri1, Naina Arora1
1School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh, India.
Abstract:
The excretory-secretory proteome plays a pivotal role in both intercellular communication during disease progression and immune escape mechanisms of various pathogens including cestode parasites like Taenia solium. The cysticerci of T. solium causes infection in the central nervous system known as neurocysticercosis (NCC), which affects a significant population in developing countries. Extracellular vesicles (EVs) are 30-150-nm-sized particles and constitute a significant part of the secretome. However, the role of EV in NCC pathogenesis remains undetermined. Here, for the first time, we report that EV from T. solium larvae is abundant in metabolites that can negatively regulate PI3K/AKT pathway, efficiently internalized by macrophages to induce AKT and mTOR degradation through auto-lysosomal route with a prominent increase in the ubiquitination of both proteins. This results in less ROS production and diminished bacterial killing capability among EV-treated macrophages. Due to this, both macro-autophagy and caspase-linked apoptosis are upregulated, with a reduction of the autophagy substrate sequestome 1. In summary, we report that T. solium EV from viable cysts attenuates the AKT-mTOR pathway thereby promoting apoptosis in macrophages, and this may exert immunosuppression during an early viable stage of the parasite in NCC, which is primarily asymptomatic. Further investigation on EV-mediated immune suppression revealed that the EV can protect the mice from DSS-induced colitis and improve colon architecture. These findings shed light on the previously unknown role of T. solium EV and the therapeutic role of their immune suppression potential.
Insights
Taenia solium larvae extracellular vesicles (EVs) suppress macrophage immune responses by degrading AKT and mTOR, promoting apoptosis. These EVs may contribute to immunosuppression during early neurocysticercosis (NCC) and offer therapeutic potential.
Area of Science:
- Parasitology
- Immunology
- Cell Biology
Background:
- Excretory-secretory products of pathogens like Taenia solium are crucial for disease progression and immune evasion.
- Neurocysticercosis (NCC), caused by T. solium cysticerci, is a significant public health issue in developing nations.
- Extracellular vesicles (EVs) are key components of the secretome, but their role in NCC pathogenesis is unknown.
Purpose of the Study:
- To investigate the role of extracellular vesicles (EVs) from Taenia solium larvae in neurocysticercosis (NCC) pathogenesis.
- To elucidate the mechanism by which T. solium EVs interact with host immune cells.
- To explore the potential therapeutic applications of T. solium EVs.
Main Methods:
- Characterization of metabolites within T. solium larval EVs.
- In vitro studies involving the internalization of EVs by macrophages.
- Analysis of key signaling pathways (PI3K/AKT/mTOR), protein degradation, reactive oxygen species (ROS) production, and apoptosis in EV-treated macrophages.
- In vivo studies using a mouse model of DSS-induced colitis.
Main Results:
- T. solium EVs contain metabolites that inhibit the PI3K/AKT pathway.
- EVs are internalized by macrophages, leading to AKT and mTOR degradation via the autolysosomal pathway and increased ubiquitination.
- EV treatment reduces macrophage ROS production and bacterial killing capacity, upregulating macro-autophagy and apoptosis.
- T. solium EVs demonstrated a protective effect in a DSS-induced colitis mouse model, improving colon architecture.
Conclusions:
- T. solium EVs from viable cysts attenuate the AKT-mTOR pathway, inducing apoptosis in macrophages and potentially mediating immunosuppression during early NCC.
- EV-mediated immunosuppression by T. solium may be a critical factor in the asymptomatic phase of NCC.
- T. solium EVs possess immunomodulatory properties with potential therapeutic applications for inflammatory conditions like colitis.
