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Silvano A, Sotillo J, Cecchi M, Loukas A, Ouedraogo M, Parenti A, Bruschi F, Torcia MG, Mangano VD. Schistosoma heamatobium tetraspanins TSP-2 and TSP-6 induce Dendritic Cells maturation, cytokine production and T helper cells differentiation in vitro. Microbes Infect 2025; 27:105439. [PMID: 39549890 DOI: 10.1016/j.micinf.2024.105439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
Urogenital schistosomiasis caused by Schistosoma haematobium is a major cause of disability in endemic areas. Despite its socio-economic burden, no vaccine exists and the parasite's immunobiology remains underexplored. Genome annotation has revealed over 40 different genes encoding tetraspanins, transmembrane proteins with known immunomodulatory properties in other plathelminthes. This study investigated the role of Sh-TSP-2, Sh-TSP-6 and Sh-TSP-23, which are expressed in the parasite's tegument and extracellular vesicles (EVs). Immature dendritic cells (DCs) from unexposed healthy donors were stimulated with these proteins to evaluate maturation maker expression and cytokine production. Also, pre-activated T CD4+ cells were stimulated with the DCs supernatant to assess cytokine gene expression. Sh-TSP-2 and Sh-TSP-6 induced maturation markers and cytokine production in DCs: Sh-TSP-2 increased CD80 and CD83 levels and the concentration of both pro-inflammatory (IL-6, TNF) and regulatory (IL-10) cytokines, while Sh-TSP-6 increased the production of IL-6. Moreover, supernatants from Sh-TSP-2 stimulated DCs induced the expression of Th1 (IFNɣ) and regulatory (IL-10) cytokines in CD4+ T cells, while Sh-TSP-6 induced Th2 (IL-4, IL-13) cytokine expression. These results provide evidence that S. haematobium tetraspanins modulate the response of human DCs and CD4+ T cells in vitro, and support Sh-TSP-2 as a promising vaccine candidate.
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Affiliation(s)
- Angela Silvano
- Dept. of Health Sciences, University of Florence, Florence, Italy
| | - Javier Sotillo
- Parasitology Reference and Research Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Marta Cecchi
- Dept. of Health Sciences, University of Florence, Florence, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Alex Loukas
- Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
| | - Mireille Ouedraogo
- Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Dep. of Public Health and Infectious Diseases, University of Rome La Sapienza, Italy; Centre National de Recherche et Formation sur le Paludisme, Ouagadougou, Burkina Faso
| | - Astrid Parenti
- Dept. of Health Sciences, University of Florence, Florence, Italy
| | - Fabrizio Bruschi
- Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | - Valentina D Mangano
- Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
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2
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Lishai EA, Ponomarev DV, Zaparina OG, Pakharukova MY. Transcriptome analysis reveals significant discrepancies between two in vitro models of host-trematode interaction. Acta Trop 2025; 262:107534. [PMID: 39864722 DOI: 10.1016/j.actatropica.2025.107534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/20/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
Cell models emulating an in vitro parasitic infection can greatly improve our understanding of helminthiases. Nonetheless, it remains challenging to select an appropriate in vitro model to study molecular pathogenesis of infections by trematodes having a complex life cycle. Therefore, adequate models are in high demand. The epidemiologically important foodborne trematode Opisthorchis felineus parasitizes bile ducts of fish-eating mammals, including humans. The human infection leads to chronic inflammation and biliary intraepithelial neoplasia, which is considered precancerous. This study was aimed at evaluating two useful in vitro research tools based on human cholangiocytes' (H69 cells') response to the trematode: coculture with live worms or incubation with parasite-derived excretory-secretory products (ESPs). We assessed H69 cells' proliferation, migration rate, cell cycle shift, and cytokine production. We also conducted genome-wide transcriptome analysis to identify affected cascades of regulatory signaling events. We demonstrated significant discrepancies between the two in vitro models of host-parasite interactions. Although differences between the two models in cell proliferation and cell migration rate were weak, there were substantial differences in the production and release of cytokines IL-6, IL-4, and TNF. A total of 144 genes in H69 cells were found to be differentially expressed after coculture with live worms, whereas 537 genes were differentially expressed after exposure to ESPs. Transcriptomic analysis revealed only 11 common upregulated genes and six common downregulated genes. Functional enrichment analysis of the gene sets also revealed some striking differences between the in vitro models. Our data will contribute to a deeper understanding of biliary neoplasia associated with liver fluke infection. This study underscores the importance of choosing an appropriate in vitro model to accurately emulate host-parasite interactions. The data also highlight the need for further investigation into the pathogenesis of the precancerous biliary lesions associated with liver fluke infection.
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Affiliation(s)
- Ekaterina A Lishai
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Akad. Lavrentiev Ave., Novosibirsk, 630090, Russia; Department of Natural Sciences, Novosibirsk State University, 2 Pirogova Str., Novosibirsk, 630090, Russia
| | - Dmitry V Ponomarev
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Akad. Lavrentiev Ave., Novosibirsk, 630090, Russia
| | - Oxana G Zaparina
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Akad. Lavrentiev Ave., Novosibirsk, 630090, Russia
| | - Maria Y Pakharukova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Akad. Lavrentiev Ave., Novosibirsk, 630090, Russia; Department of Natural Sciences, Novosibirsk State University, 2 Pirogova Str., Novosibirsk, 630090, Russia.
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Luan X, Wang X, Bian G, Li X, Gao Z, Liu Z, Zhang Z, Han T, Zhao J, Zhao H, Luan X, Zhu W, Dong L, Guo F. Exosome applications for the diagnosis and treatment of pancreatic ductal adenocarcinoma: An update (Review). Oncol Rep 2025; 53:13. [PMID: 39575479 PMCID: PMC11605277 DOI: 10.3892/or.2024.8846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.
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Affiliation(s)
- Xinchi Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuezhe Wang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Gang Bian
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Xiaoxuan Li
- Department of Oncology, Key Laboratory of Cancer Molecular and Translational Research, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China
| | - Ziru Gao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zijiao Liu
- School of Clinical and Basic Medicine and Institute of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Zhishang Zhang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Tianyue Han
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Jinpeng Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Hongjiao Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xinyue Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wuhui Zhu
- Department of Hepatobiliary surgery, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Lili Dong
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Feifei Guo
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
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Chan TCL, Yagound B, Brown GP, Eyck HJF, Shine R, Rollins LA. Infection by the Lungworm Rhabdias pseudosphaerocephala Affects the Expression of Immune-Related microRNAs by Its Co-Evolved Host, the Cane Toad Rhinella marina. Mol Ecol 2025; 34:e17587. [PMID: 39544005 DOI: 10.1111/mec.17587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/09/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
Parasites may suppress the immune function of infected hosts using microRNAs (miRNAs) to prevent protein production. Nonetheless, little is known about the diversity of miRNAs and their mode(s) of action. In this study, we investigated the effects of infection by a parasitic lungworm (Rhabdias pseudosphaerocephala) on miRNA and mRNA expression of its host, the invasive cane toad (Rhinella marina). To investigate the cane toad's innate and adaptive immune response to this parasite, we compared miRNA and mRNA expression in naïve toads that had never been infected by lungworms to toads that were infected with lungworms for the first time in their lives, and toads that were infected the second time in their lives (i.e., had two consecutive infections). In total, we identified 101 known miRNAs and 86 potential novel miRNAs. Compared to uninfected and single-infection toads, multiple-infection animals drastically downregulated three miRNAs. These miRNAs were associated with gene pathways related to the immune response, potentially reflecting the immunosuppression of cane toads by their parasites. Infected hosts did not respond with substantially differential mRNA transcription; only one gene was differentially expressed between control and single-infection hosts. Our study suggests that miRNA may play an important role in mediating host-parasite interactions in a system in which an ongoing range expansion by the host has generated substantial divergence in host-parasite interactions.
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Affiliation(s)
- Tsering C L Chan
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
| | - Boris Yagound
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
| | - Gregory P Brown
- School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Harrison J F Eyck
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
| | - Richard Shine
- School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Lee A Rollins
- Ecology & Evolution Research Centre, School of Biological, Earth and Environmental Sciences, University of New South Wales, UNSW, Sydney, New South Wales, Australia
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Chavda VP, Luo G, Bezbaruah R, Kalita T, Sarma A, Deka G, Duo Y, Das BK, Shah Y, Postwala H. Unveiling the promise: Exosomes as game-changers in anti-infective therapy. EXPLORATION (BEIJING, CHINA) 2024; 4:20230139. [PMID: 39439498 PMCID: PMC11491308 DOI: 10.1002/exp.20230139] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 01/23/2024] [Indexed: 10/25/2024]
Abstract
Extracellular vesicles (EVs)-based intercellular communication (through exosomes, microvesicles, and apoptotic bodies) is conserved across all kingdoms of life. In recent years, exosomes have gained much attention for targeted pharmaceutical administration due to their unique features, nanoscale size, and capacity to significantly contribute to cellular communication. As drug delivery vehicles, exosomes have several advantages over alternative nanoparticulate drug delivery technologies. A key advantage lies in their comparable makeup to the body's cells, which makes them non-immunogenic. However, exosomes vesicles face several challenges, including a lack of an effective and standard production technique, decreased drug loading capacity, limited characterization techniques, and underdeveloped isolation and purification procedures. Exosomes are well known for their long-term safety and natural ability to transport intercellular nucleic acids and medicinal compounds across the blood-brain-barrier (BBB). Therefore, in addition to revealing new insights into exosomes' distinctiveness, the growing availability of new analytical tools may drive the development of next-generation synthetic systems. Herein, light is shed on exosomes as drug delivery vehicles in anti-infective therapy by reviewing the literature on primary articles published between 2002 and 2023. Additionally, the benefits and limitations of employing exosomes as vehicles for therapeutic drug delivery are also discussed.
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Affiliation(s)
- Vivek P. Chavda
- Department of Pharmaceutics and Pharmaceutical TechnologyL. M. College of PharmacyAhmedabadGujaratIndia
| | - Guanghong Luo
- Department of Radiation OncologyShenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdongChina
| | - Rajashri Bezbaruah
- Department of Pharmaceutical SciencesFaculty of Science and EngineeringDibrugarh UniversityDibrugarhAssamIndia
| | - Tutumoni Kalita
- School of Pharmaceutical SciencesGirijananda Chowdhury University, AzaraGuwahatiAssamIndia
| | - Anupam Sarma
- School of Pharmaceutical SciencesGirijananda Chowdhury University, AzaraGuwahatiAssamIndia
| | - Gitima Deka
- College of PharmacyYeungnam UniversityGyeonsanRepublic of Korea
| | - Yanhong Duo
- Wyss Institute for Biologically Inspired EngineeringHarvard UniversityBostonMassachusettsUSA
| | - Bhrigu Kumar Das
- School of Pharmaceutical SciencesGirijananda Chowdhury University, AzaraGuwahatiAssamIndia
| | - Yesha Shah
- PharmD SectionL. M. College of PharmacyAhmedabadGujaratIndia
| | - Humzah Postwala
- PharmD SectionL. M. College of PharmacyAhmedabadGujaratIndia
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6
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Ghazi B, Harmak Z, Rghioui M, Kone AS, El Ghanmi A, Badou A. Decoding the secret of extracellular vesicles in the immune tumor microenvironment of the glioblastoma: on the border of kingdoms. Front Immunol 2024; 15:1423232. [PMID: 39267734 PMCID: PMC11390556 DOI: 10.3389/fimmu.2024.1423232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 08/06/2024] [Indexed: 09/15/2024] Open
Abstract
Over the last decades, extracellular vesicles (EVs) have become increasingly popular for their roles in various pathologies, including cancer and neurological and immunological disorders. EVs have been considered for a long time as a means for normal cells to get rid of molecules it no longer needs. It is now well established that EVs play their biological roles also following uptake or by the interaction of EV surface proteins with cellular receptors and membranes. In this review, we summarize the current status of EV production and secretion in glioblastoma, the most aggressive type of glioma associated with high mortality. The main purpose is to shed light on the EVs as a universal mediator of interkingdom and intrakingdom communication in the context of tumor microenvironment heterogeneity. We focus on the immunomodulatory EV functions in glioblastoma-immune cross-talk to enhance immune escape and reprogram tumor-infiltrating immune cells. We critically examine the evidence that GBM-, immune cell-, and microbiome-derived EVs impact local tumor microenvironment and host immune responses, and can enter the circulatory system to disseminate and drive premetastatic niche formation in distant organs. Taking into account the current state of the art in intratumoral microbiome studies, we discuss the emerging role of bacterial EV in glioblastoma and its response to current and future therapies including immunotherapies.
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Affiliation(s)
- Bouchra Ghazi
- Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine, Mohammed VI University of Sciences and Health, Casablanca, Morocco
- Mohammed VI International University Hospital, Bouskoura, Morocco
| | - Zakia Harmak
- Immuno-genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Mounir Rghioui
- Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine, Mohammed VI University of Sciences and Health, Casablanca, Morocco
- Mohammed VI International University Hospital, Bouskoura, Morocco
| | - Abdou-Samad Kone
- Immuno-genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Adil El Ghanmi
- Immunopathology-Immunotherapy-Immunomonitoring Laboratory, Faculty of Medicine, Mohammed VI University of Sciences and Health, Casablanca, Morocco
- Mohammed VI International University Hospital, Bouskoura, Morocco
| | - Abdallah Badou
- Immuno-genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
- Mohammed VI Center for Research and Innovation, Rabat, Morocco
- Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
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7
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Barnadas-Carceller B, Del Portillo HA, Fernandez-Becerra C. Extracellular vesicles as biomarkers in parasitic disease diagnosis. CURRENT TOPICS IN MEMBRANES 2024; 94:187-223. [PMID: 39370207 DOI: 10.1016/bs.ctm.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Parasitic diseases constitute a major global health problem, affecting millions of people worldwide. Recent advances in the study of extracellular vesicles (EVs) have opened up new strategies for biomarker discovery in protozoan and helminth infections. Analyses of EVs in cultures and biological fluids have identified numerous potential biomarkers that could be useful for early and differential diagnosis, monitoring therapeutic responses, and the overall management and control of these diseases. Despite the potential of these biomarkers, several challenges must be addressed, including limited research, the need for standardized protocols, and the reproducibility of results across studies. In many parasitic infections, EVs have been obtained from various sample types, including plasma from human patients and mouse models, as well as cultures of the parasites at different stages. EVs were isolated by various methods and predominantly characterized through proteomic analysis or RNA sequencing to assess their cargo and identify potential biomarkers. These biomarker candidates were investigated and validated using different assays such as ELISA, Western Blot, and ROC curves. Overall, the use of EVs is considered a promising new diagnostic strategy for parasite infections, but further research with larger cohorts, standardized methods, and additional validation tests are essential for effective diagnosis and management of these diseases.
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Affiliation(s)
- Berta Barnadas-Carceller
- ISGlobal, Barcelona Institute for Global Health, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain; IGTP Institut d'Investigació Germans Trias I Pujol, Badalona, Barcelona, Spain
| | - Hernando A Del Portillo
- ISGlobal, Barcelona Institute for Global Health, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain; IGTP Institut d'Investigació Germans Trias I Pujol, Badalona, Barcelona, Spain; ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Carmen Fernandez-Becerra
- ISGlobal, Barcelona Institute for Global Health, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain; IGTP Institut d'Investigació Germans Trias I Pujol, Badalona, Barcelona, Spain; CIBERINFEC, ISCIII-CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
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Qadeer A, Wajid A, Rafey HA, Nawaz S, Khan S, Rahman SU, Alzahrani KJ, Khan MZ, Alsabi MNS, Ullah H, Safi SZ, Xia Z, Zahoor M. Exploring extracellular vesicles in zoonotic helminth biology: implications for diagnosis, therapeutic and delivery. Front Cell Infect Microbiol 2024; 14:1424838. [PMID: 39165921 PMCID: PMC11333462 DOI: 10.3389/fcimb.2024.1424838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 07/03/2024] [Indexed: 08/22/2024] Open
Abstract
Extracellular vesicles (EVs) have emerged as key intercellular communication and pathogenesis mediators. Parasitic organisms' helminths, cause widespread infections with significant health impacts worldwide. Recent research has shed light on the role of EVs in the lifecycle, immune evasion, and disease progression of these parasitic organisms. These tiny membrane-bound organelles including microvesicles and exosomes, facilitate the transfer of proteins, lipids, mRNAs, and microRNAs between cells. EVs have been isolated from various bodily fluids, offering a potential diagnostic and therapeutic avenue for combating infectious agents. According to recent research, EVs from helminths hold great promise in the diagnosis of parasitic infections due to their specificity, early detection capabilities, accessibility, and the potential for staging and monitoring infections, promote intercellular communication, and are a viable therapeutic tool for the treatment of infectious agents. Exploring host-parasite interactions has identified promising new targets for diagnostic, therapy, and vaccine development against helminths. This literature review delves into EVS's origin, nature, biogenesis, and composition in these parasitic organisms. It also highlights the proteins and miRNAs involved in EV release, providing a comprehensive summary of the latest findings on the significance of EVs in the biology of helminths, promising targets for therapeutic and diagnostic biomarkers.
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Affiliation(s)
- Abdul Qadeer
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Abdul Wajid
- Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan
| | - Hafiz Abdul Rafey
- Shifa College of Pharmaceutical Sciences, Faculty of Pharmaceutical and Allied Health Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Saqib Nawaz
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Sawar Khan
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Sajid Ur Rahman
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Khalid J. Alzahrani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Muhammad Zahoor Khan
- College of Agricultural Science and Engineering, Liaocheng University, Liaocheng, Shandong, China
| | - Mohammad Nafi Solaiman Alsabi
- Department of Basic Veterinary Medical Sciences, Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Hanif Ullah
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China
| | - Sher Zaman Safi
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor, Malaysia
| | - Zanxian Xia
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China
| | - Muhammad Zahoor
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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9
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Pinheiro AAS, Torrecilhas AC, Souza BSDF, Cruz FF, Guedes HLDM, Ramos TD, Lopes‐Pacheco M, Caruso‐Neves C, Rocco PRM. Potential of extracellular vesicles in the pathogenesis, diagnosis and therapy for parasitic diseases. J Extracell Vesicles 2024; 13:e12496. [PMID: 39113589 PMCID: PMC11306921 DOI: 10.1002/jev2.12496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/11/2024] [Indexed: 08/11/2024] Open
Abstract
Parasitic diseases have a significant impact on human and animal health, representing a major hazard to the public and causing economic and health damage worldwide. Extracellular vesicles (EVs) have long been recognized as diagnostic and therapeutic tools but are now also known to be implicated in the natural history of parasitic diseases and host immune response modulation. Studies have shown that EVs play a role in parasitic disease development by interacting with parasites and communicating with other types of cells. This review highlights the most recent research on EVs and their role in several aspects of parasite-host interactions in five key parasitic diseases: Chagas disease, malaria, toxoplasmosis, leishmaniasis and helminthiases. We also discuss the potential use of EVs as diagnostic tools or treatment options for these infectious diseases.
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Affiliation(s)
- Ana Acacia Sá Pinheiro
- Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Rio de Janeiro Innovation Network in Nanosystems for Health‐NanoSAÚDE/Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Rio de JaneiroBrazil
| | - Ana Claudia Torrecilhas
- Departamento de Ciências FarmacêuticasDiadema Campus, Instituto de Ciências Ambientais, Químicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)DiademaSão PauloBrazil
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell TherapySão Rafael HospitalSalvadorBrazil
- D'Or Institute for Research and Education (IDOR)SalvadorBrazil
| | - Fernanda Ferreira Cruz
- Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Rio de Janeiro Innovation Network in Nanosystems for Health‐NanoSAÚDE/Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Rio de JaneiroBrazil
| | - Herbert Leonel de Matos Guedes
- Instituto de Microbiologia Paulo de Goés (IMPG)Universidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Fundação Oswaldo Cruz (FIOCRUZ)Instituto Oswaldo Cruz (IOC)Rio de JaneiroBrazil
| | - Tadeu Diniz Ramos
- Instituto de Microbiologia Paulo de Goés (IMPG)Universidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Fundação Oswaldo Cruz (FIOCRUZ)Instituto Oswaldo Cruz (IOC)Rio de JaneiroBrazil
| | - Miqueias Lopes‐Pacheco
- Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Deparment of PediatricsCenter for Cystic Fibrosis and Airway Disease ResearchEmory University School of MedicineAtlantaGeorgiaUSA
| | - Celso Caruso‐Neves
- Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Rio de Janeiro Innovation Network in Nanosystems for Health‐NanoSAÚDE/Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Rio de JaneiroBrazil
- National Institute of Science and Technology for Regenerative MedicineINCT‐REGENERARio de JaneiroBrazil
| | - Patricia R. M. Rocco
- Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
- Rio de Janeiro Innovation Network in Nanosystems for Health‐NanoSAÚDE/Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Rio de JaneiroBrazil
- National Institute of Science and Technology for Regenerative MedicineINCT‐REGENERARio de JaneiroBrazil
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10
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Zhou W, Li X, Yang X, Ye B. The In Vitro Promoting Angiogenesis Roles of Exosomes Derived from the Protoscoleces of Echinococcus multilocularis. J Microbiol Biotechnol 2024; 34:1410-1418. [PMID: 38858095 PMCID: PMC11294651 DOI: 10.4014/jmb.2403.03042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/05/2024] [Accepted: 05/13/2024] [Indexed: 06/12/2024]
Abstract
Alveolar echinococcosis (AE) is a persistent parasite condition that causes the formation of tumor-like growths. It is a challenge to treat the disease. These growths need neovascularization to get their oxygen and nutrients, and the disease is prolonged and severe. Considerable research has been conducted on exosomes and their interactions with Echinococcus multilocularis in the context of immunological evasion by the host. However, the extent of their involvement in angiogenesis needs to be conducted. The primary objective of this investigation was to preliminarily explore the effect of exosomes produced from E. multilocularis protoscoleces (PSC-exo) on angiogenesis, to elucidate the mechanism of their roles in the regulation of the downstream pathway of VEGFA activation, and to provide ideas for the development of novel treatments for AE. The study evaluated the impact of PSC-exo increases proliferation, migration, invasion, and tube formation of HUVECs at concentrations of up to 50 μg/ml. In addition, the study sought to validate the findings in vivo. This effect involved increased VEGFA expression at gene and protein levels and AKT/mTOR pathway activation. PSC-exo are crucial in promoting angiogenesis through VEGFA upregulation and AKT/mTOR signaling. This research contributes to our knowledge of neovascularization in AE.
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Affiliation(s)
- Wenjing Zhou
- Department of Pathogen Biology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xiang Li
- Department of Pathogen Biology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xinqi Yang
- Department of Pathogen Biology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Bin Ye
- Department of Pathogen Biology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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11
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Kochanowsky JA, Mira PM, Elikaee S, Muratore K, Rai AK, Riestra AM, Johnson PJ. Trichomonas vaginalis extracellular vesicles up-regulate and directly transfer adherence factors promoting host cell colonization. Proc Natl Acad Sci U S A 2024; 121:e2401159121. [PMID: 38865261 PMCID: PMC11194581 DOI: 10.1073/pnas.2401159121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/16/2024] [Indexed: 06/14/2024] Open
Abstract
Trichomonas vaginalis, a common sexually transmitted parasite that colonizes the human urogenital tract, secretes extracellular vesicles (TvEVs) that are taken up by human cells and are speculated to be taken up by parasites as well. While the crosstalk between TvEVs and human cells has led to insight into host:parasite interactions, roles for TvEVs in infection have largely been one-sided, with little known about the effect of TvEV uptake by T. vaginalis. Approximately 11% of infections are found to be coinfections of multiple T. vaginalis strains. Clinical isolates often differ in their adherence to and cytolysis of host cells, underscoring the importance of understanding the effects of TvEV uptake within the parasite population. To address this question, our lab tested the ability of a less adherent strain of T. vaginalis, G3, to take up fluorescently labeled TvEVs derived from both itself (G3-EVs) and TvEVs from a more adherent strain of the parasite (B7RC2-EVs). Here, we showed that TvEVs generated from the more adherent strain are internalized more efficiently compared to the less adherent strain. Additionally, preincubation of G3 parasites with B7RC2-EVs increases parasite aggregation and adherence to host cells. Transcriptomics revealed that TvEVs up-regulate expression of predicted parasite membrane proteins and identified an adherence factor, heteropolysaccharide binding protein (HPB2). Finally, using comparative proteomics and superresolution microscopy, we demonstrated direct transfer of an adherence factor, cadherin-like protein, from TvEVs to the recipient parasite's surface. This work identifies TvEVs as a mediator of parasite:parasite communication that may impact pathogenesis during mixed infections.
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Affiliation(s)
- Joshua A. Kochanowsky
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
| | - Portia M. Mira
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
| | - Samira Elikaee
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
| | - Katherine Muratore
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
| | - Anand Kumar Rai
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
| | - Angelica M. Riestra
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
- Department of Biology, San Diego State University, San Diego, CA92182
| | - Patricia J. Johnson
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA90095
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12
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Wu H, Giri BR, Li H, Zheng Y, Yan X, Cheng G. Schistosoma japonicum extracellular vesicle proteins serve as effective biomarkers for diagnosing parasite infection. Front Cell Infect Microbiol 2024; 14:1391168. [PMID: 38817446 PMCID: PMC11137203 DOI: 10.3389/fcimb.2024.1391168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 04/30/2024] [Indexed: 06/01/2024] Open
Abstract
Schistosoma species are the causative agent of schistosomiasis and shows worldwide distribution. There is a great need to develop a sensitive diagnostic approach for controlling the disease. Previously, we identified large numbers of Extracellular Vesicle (EV) proteins from Schistosoma japonicum (S. japonicum), but rarely these proteins have been evaluated for their diagnostic potential. In the present study, we performed bioinformatic analyses of S. japonicum identified EV-associated proteins from the previous study and then identified Schistosoma-specific proteins with potentially secreted capability. Among them, we selected SJCHGC02838 protein, SJCHGC05593 protein, SJCHGC05668 protein and a hypothetical protein (SJHYP) to evaluate their diagnostic potential for detecting S. japonicum infection. First, we determined the expression of these four proteins at the transcript levels using qRT-PCR and revealed that all these genes showed higher expression in adult stage. Then, we cloned the full-length cDNA for each protein into a prokaryotic expression vector and successfully generated the recombinant proteins. Upon the purification of recombinant proteins, we developed an indirect ELISA method to evaluate the diagnostic potential of these purified recombinant proteins. The results showed high sensitivity for detecting Schistosoma infection. Additionally, these proteins also displayed a good potential for detecting Schistosoma infection, especially SJCHGC05668 protein at an early stage. The diagnostic potentials of these recombinant proteins were further evaluated by Western blot and comparatively analyzed by our previously developed cfDNA methods.
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Affiliation(s)
- Huixin Wu
- Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bikash R. Giri
- Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Zoology, Kuntala Kumari Sabat (KKS) Women’s College, Balasore, Odisha, India
| | - Huimin Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai, China
| | - Yameng Zheng
- Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoli Yan
- Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guofeng Cheng
- Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
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13
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Cui Z, Yu W, Wang Z, Kong F, Ye G, Yan J, Wu D, Du F, Pang M, Shi D, Ren L. Molecular analyses of exosome-derived miRNAs revealed reduced expression of miR-184-3p and decreased exosome concentration in patients with alveolar echinococcosis. Exp Parasitol 2024; 260:108734. [PMID: 38490318 DOI: 10.1016/j.exppara.2024.108734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 12/17/2023] [Accepted: 03/05/2024] [Indexed: 03/17/2024]
Abstract
Both E. multilocularis and host-derived exosomes are involved in the pathogenic process of alveolar echinococcosis (AE). Exosomes secrete miRNAs that have regulatory roles in host-pathogen interactions in multiple ways. In the present study, we collected and purified supernatants of E. multilocularis cultures, as well as human plasma exosomes. High-throughput sequencing showed the identities of 45 exosomal miRNAs in E. multilocularis. The lengths of these miRNAs ranged from 19 to 25 nucleotides (nt), with the majority (n = 18) measuring 22 nt. Notably, emu-let-7-5p emerged as the most abundant among these miRNAs, with a detected count of 33,097 and also length of 22 nt. Nanoparticle tracking analysis (NTA) showed that the concentration of exosomes in the plasma of AE patients was lower compared to that in the healthy individuals. This result suggested that the concentration of plasma exosomes was able to distinguish AE patients from healthy individuals. Using qRT-PCR to assess the relative expression of 10 miRNAs of E. multilocularis, we showed that the expression of miR-184-3p was downregulated significantly in the exosomes of plasma from AE patients compared to that in the control group. In summary, this study indicates that AE induces a reduction in the concentration of human plasma exosomes, as well as downregulating miR-184-3p in infected individuals.
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Affiliation(s)
- Ziyan Cui
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Department of Postgraduate, Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Wenhao Yu
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Zhixin Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Fanyu Kong
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Gengbo Ye
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Department of Postgraduate, Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Jican Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Department of Postgraduate, Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Defang Wu
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Fei Du
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Department of Postgraduate, Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Mingquan Pang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Dalin Shi
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China
| | - Li Ren
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Qinghai, 810001, China; Qinghai Research Key Laboratory for Echinococcosis, Qinghai, 810001, China.
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14
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Teymouri S, Pourhajibagher M, Bahador A. Exosomes: Friends or Foes in Microbial Infections? Infect Disord Drug Targets 2024; 24:e170124225730. [PMID: 38317472 DOI: 10.2174/0118715265264388231128045954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 02/07/2024]
Abstract
The use of new approaches is necessary to address the global issue of infections caused by drug-resistant pathogens. Antimicrobial photodynamic therapy (aPDT) is a promising approach that reduces the emergence of drug resistance, and no resistance has been reported thus far. APDT involves using a photosensitizer (PS), a light source, and oxygen. The mechanism of aPDT is that a specific wavelength of light is directed at the PS in the presence of oxygen, which activates the PS and generates reactive oxygen species (ROS), consequently causing damage to microbial cells. However, due to the PS's poor stability, low solubility in water, and limited bioavailability, it is necessary to employ drug delivery platforms to enhance the effectiveness of PS in photodynamic therapy (PDT). Exosomes are considered a desirable carrier for PS due to their specific characteristics, such as low immunogenicity, innate stability, and high ability to penetrate cells, making them a promising platform for drug delivery. Additionally, exosomes also possess antimicrobial properties, although in some cases, they may enhance microbial pathogenicity. As there are limited studies on the use of exosomes for drug delivery in microbial infections, this review aims to present significant points that can provide accurate insights.
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Affiliation(s)
- Samane Teymouri
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Pourhajibagher
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Bahador
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Fellowship in Clinical Laboratory Sciences, BioHealth Lab, Tehran, Iran
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15
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Liao Y, Zhu Z, Liu Y, Wu J, Li D, Li Z, Xu J, Yang R, Wang L. Schistosome egg-derived extracellular vesicles deliver Sja-miR-71a inhibits host macrophage and neutrophil extracellular traps via targeting Sema4D. Cell Commun Signal 2023; 21:366. [PMID: 38129877 PMCID: PMC10734185 DOI: 10.1186/s12964-023-01395-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/11/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Macrophages and neutrophils are rapidly recruited around Schistosome eggs to form granulomas. Extracellular traps (ETs) of macrophages and neutrophils are part of the pathogen clearance armamentarium of leukocytes. Schistosome eggs possess the ability to resist attack by the host's immune cells and survive by employing various immune evasion mechanisms, including the release of extracellular vesicles (EVs). However, the specific mechanisms by which Schistosome egg-derived EVs (E-EVs) evade the immune response and resist attack from macrophage and neutrophil ETs remain poorly understood. In this study, we aimed to investigate the association between E-EVs and macrophage/neutrophil ETs. METHODS EVs were isolated from the culture supernatant of S. japonicum eggs and treated macrophages and neutrophils with E-EVs and Sja-miR-71a. The formation of ETs was then observed. Additionally, we infected mice with S. japonicum, administered HBAAV2/9-Sja-miR-71a, and the formation of macrophage ETs (METs) and neutrophil ETs (NETs) in the livers was measured. Sema4D-knockout mice, RNA sequencing, and trans-well assay were used to clarify Sja-miR-71a in E-EVs inhibits METs and NETs formation via the Sema4D/ PPAR-γ/ IL-10 axis. RESULTS Our findings revealed that E-EVs were internalized by macrophages and neutrophils, leading to the inhibition of METs and NETs formation. The highly expressed Sja-miR-71a in E-EVs targeted Sema4D, resulting in the up-regulation of IL-10 and subsequent inhibition of METs and NETs formation. Sema4D knockout up-regulated IL-10 expression and inhibited the formation of METs and NETs. Furthermore, we further demonstrated that Sja-miR-71a inhibits METs and NETs formation via the Sema4D/ PPAR-γ/ IL-10 axis. CONCLUSIONS In summary, our findings provide new insights into the immune evasion abilities of Schistosome eggs by demonstrating their ability to inhibit the formation of METs and NETs through the secretion of EVs. This study enhances our understanding of the host-pathogen interaction and may have implications for the development of novel therapeutic approaches. Video Abstract.
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Affiliation(s)
- Yao Liao
- Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Zifeng Zhu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuheng Liu
- Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Ji Wu
- Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Dinghao Li
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhen Li
- Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Junhao Xu
- Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Ruibing Yang
- Guangzhou KingMed Diagnostic Laboratory Ltd, Guangzhou, 510320, China.
| | - Lifu Wang
- Guangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
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16
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Fernandez‐Becerra C, Xander P, Alfandari D, Dong G, Aparici‐Herraiz I, Rosenhek‐Goldian I, Shokouhy M, Gualdron‐Lopez M, Lozano N, Cortes‐Serra N, Karam PA, Meneghetti P, Madeira RP, Porat Z, Soares RP, Costa AO, Rafati S, da Silva A, Santarém N, Fernandez‐Prada C, Ramirez MI, Bernal D, Marcilla A, Pereira‐Chioccola VL, Alves LR, Portillo HD, Regev‐Rudzki N, de Almeida IC, Schenkman S, Olivier M, Torrecilhas AC. Guidelines for the purification and characterization of extracellular vesicles of parasites. JOURNAL OF EXTRACELLULAR BIOLOGY 2023; 2:e117. [PMID: 38939734 PMCID: PMC11080789 DOI: 10.1002/jex2.117] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 08/21/2023] [Accepted: 09/14/2023] [Indexed: 06/29/2024]
Abstract
Parasites are responsible for the most neglected tropical diseases, affecting over a billion people worldwide (WHO, 2015) and accounting for billions of cases a year and responsible for several millions of deaths. Research on extracellular vesicles (EVs) has increased in recent years and demonstrated that EVs shed by pathogenic parasites interact with host cells playing an important role in the parasite's survival, such as facilitation of infection, immunomodulation, parasite adaptation to the host environment and the transfer of drug resistance factors. Thus, EVs released by parasites mediate parasite-parasite and parasite-host intercellular communication. In addition, they are being explored as biomarkers of asymptomatic infections and disease prognosis after drug treatment. However, most current protocols used for the isolation, size determination, quantification and characterization of molecular cargo of EVs lack greater rigor, standardization, and adequate quality controls to certify the enrichment or purity of the ensuing bioproducts. We are now initiating major guidelines based on the evolution of collective knowledge in recent years. The main points covered in this position paper are methods for the isolation and molecular characterization of EVs obtained from parasite-infected cell cultures, experimental animals, and patients. The guideline also includes a discussion of suggested protocols and functional assays in host cells.
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Affiliation(s)
- Carmen Fernandez‐Becerra
- ISGlobal, Barcelona Institute for Global HealthHospital Clínic‐Universitatde BarcelonaBarcelonaSpain
- IGTP Institut d'Investigació Germans Trias i PujolBadalona (Barcelona)Spain
- CIBERINFECISCIII‐CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos IIIMadridSpain
| | - Patrícia Xander
- Departamento de Ciências FarmacêuticasLaboratório de Imunologia Celular e Bioquímica de Fungos e ProtozoáriosDepartamento de Ciências FarmacêuticasInstituto de Ciências AmbientaisQuímicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
| | - Daniel Alfandari
- Department of Biomolecular SciencesWeizmann Institute of Science (WIS)RehovotIsrael
| | - George Dong
- The Research Institute of the McGill University Health CentreMcGill UniversityMontréalQuébecCanada
| | - Iris Aparici‐Herraiz
- ISGlobal, Barcelona Institute for Global HealthHospital Clínic‐Universitatde BarcelonaBarcelonaSpain
| | | | - Mehrdad Shokouhy
- Department of Immunotherapy and Leishmania Vaccine ResearchPasteur Institute of IranTehranIran
| | - Melisa Gualdron‐Lopez
- ISGlobal, Barcelona Institute for Global HealthHospital Clínic‐Universitatde BarcelonaBarcelonaSpain
| | - Nicholy Lozano
- Departamento de Ciências FarmacêuticasLaboratório de Imunologia Celular e Bioquímica de Fungos e ProtozoáriosDepartamento de Ciências FarmacêuticasInstituto de Ciências AmbientaisQuímicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
| | - Nuria Cortes‐Serra
- ISGlobal, Barcelona Institute for Global HealthHospital Clínic‐Universitatde BarcelonaBarcelonaSpain
| | - Paula Abou Karam
- Department of Biomolecular SciencesWeizmann Institute of Science (WIS)RehovotIsrael
| | - Paula Meneghetti
- Departamento de Ciências FarmacêuticasLaboratório de Imunologia Celular e Bioquímica de Fungos e ProtozoáriosDepartamento de Ciências FarmacêuticasInstituto de Ciências AmbientaisQuímicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
| | - Rafael Pedro Madeira
- Departamento de Ciências FarmacêuticasLaboratório de Imunologia Celular e Bioquímica de Fungos e ProtozoáriosDepartamento de Ciências FarmacêuticasInstituto de Ciências AmbientaisQuímicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
| | - Ziv Porat
- Flow Cytometry UnitLife Sciences Core Facilities, WISRehovotIsrael
| | | | - Adriana Oliveira Costa
- Departamento de Análises Clínicas e ToxicológicasFaculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG)Belo HorizonteMinas GeraisBrasil
| | - Sima Rafati
- Department of Immunotherapy and Leishmania Vaccine ResearchPasteur Institute of IranTehranIran
| | - Anabela‐Cordeiro da Silva
- Host‐Parasite Interactions GroupInstitute of Research and Innovation in HealthUniversity of PortoPortoPortugal
- Department of Biological SciencesFaculty of PharmacyUniversity of PortoPortoPortugal
| | - Nuno Santarém
- Host‐Parasite Interactions GroupInstitute of Research and Innovation in HealthUniversity of PortoPortoPortugal
- Department of Biological SciencesFaculty of PharmacyUniversity of PortoPortoPortugal
| | | | - Marcel I. Ramirez
- EVAHPI ‐ Extracellular Vesicles and Host‐Parasite Interactions Research Group Laboratório de Biologia Molecular e Sistemática de TripanossomatideosInstituto Carlos Chagas‐FiocruzCuritibaParanáBrasil
| | - Dolores Bernal
- Departament de Bioquímica i Biologia Molecular, Facultat de Ciències BiològiquesUniversitat de ValènciaBurjassotValenciaSpain
| | - Antonio Marcilla
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i ParasitologiaUniversitat de ValènciaBurjassotValenciaSpain
| | - Vera Lucia Pereira‐Chioccola
- Laboratório de Biologia Molecular de Parasitas e Fungos, Centro de Parasitologia e MicologiaInstituto Adolfo Lutz (IAL)São PauloBrasil
| | - Lysangela Ronalte Alves
- Laboratório de Regulação da Expressão GênicaInstituto Carlos ChagasFiocruz ParanáCuritibaBrazil
- Research Center in Infectious DiseasesDivision of Infectious Disease and Immunity CHU de Quebec Research CenterDepartment of MicrobiologyInfectious Disease and ImmunologyFaculty of MedicineUniversity LavalQuebec CityQuebecCanada
| | - Hernando Del Portillo
- ISGlobal, Barcelona Institute for Global HealthHospital Clínic‐Universitatde BarcelonaBarcelonaSpain
- IGTP Institut d'Investigació Germans Trias i PujolBadalona (Barcelona)Spain
- ICREA Institució Catalana de Recerca i Estudis Avanc¸ats (ICREA)BarcelonaSpain
| | - Neta Regev‐Rudzki
- Department of Biomolecular SciencesWeizmann Institute of Science (WIS)RehovotIsrael
| | - Igor Correia de Almeida
- Department of Biological SciencesBorder Biomedical Research CenterThe University of Texas at El PasoEl PasoTexasUSA
| | - Sergio Schenkman
- Departamento de MicrobiologiaImunologia e Parasitologia, UNIFESPSão PauloBrazil
| | - Martin Olivier
- The Research Institute of the McGill University Health CentreMcGill UniversityMontréalQuébecCanada
| | - Ana Claudia Torrecilhas
- Departamento de Ciências FarmacêuticasLaboratório de Imunologia Celular e Bioquímica de Fungos e ProtozoáriosDepartamento de Ciências FarmacêuticasInstituto de Ciências AmbientaisQuímicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
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17
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Wang L, Liu T, Pu G, Chen G, Li H, Zhang S, Li Y, Luo X. Global profiling of miRNA and protein expression patterns in rabbit peritoneal macrophages treated with exosomes derived from Taenia pisiformis cysticercus. Genomics 2023; 115:110690. [PMID: 37488054 DOI: 10.1016/j.ygeno.2023.110690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/27/2023] [Accepted: 07/21/2023] [Indexed: 07/26/2023]
Abstract
Infection of Taenia pisiformis cysticercus is very frequently found in lagomorphs and causes serious economic losses to rabbit breeding industry. T. pisiformis cysticercus has evolved numerous strategies to manipulate their hosts. The release of exosomes is of importance in the interaction between host and parasite. However, the mechanism by which T. pisiformis cysticercus evades the host immune system for long-term survival within the host remains unclear. Using small RNA sequencing and TMT labelling proteomic, we profiled the expression patterns of miRNAs and proteins in rabbit peritoneal macrophages treated with T. pisiformis cysticercus exosomes. Seven differentially expressed (DE)-miRNAs and six DE-proteins were randomly selected to validate the accuracy of the sequencing data by qRT-PCR or western blot. Functions of DE-miRNAs and proteins were analyzed using public data bases. And DE-miRNAs-DE-proteins correlation network were established. CCK-8 assay was used to evaluate the effect of exosomes on macrophages proliferation. Cell cycle of macrophages, isolated from T. pisiformis-infected rabbits, was determined using flow cytometry. A total of 21 miRNAs were significantly differentially expressed, including three worm-derived miRNAs. The expressions of miRNAs and proteins were consistent with the sequencing results. DE-miRNAs targets were related to cell proliferation and apoptosis. Exosomes treatment resulted in a decrease of macrophages proliferation. In vivo, T. pisiformis cysticercus significantly induced S phase cell arrest. Moreover, DE-proteins were related to production of interferon-gamma and interleukin-12, and immunoregulation. Correlation network analysis revealed a negative correlation relationship between DE-miRNAs and DE-proteins. Among them, novel334 and tpi-let-7-5p have potential regulatory effects on IL1β and NFκB2 respectively, which imply that novel334-IL1β/tpi-let-7-5p-NFκB2 axis may be an important way that T. pisiformis cysticercus modulates host immune response through exosomes. Further understanding of these potential regulatory mechanisms will contribute to clarify the mechanism of escape mediated by T. pisiformis exosomes.
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Affiliation(s)
- Liqun Wang
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Tingli Liu
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Guiting Pu
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Guoliang Chen
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Hong Li
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Shaohua Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Yanping Li
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China.
| | - Xuenong Luo
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, China.
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Doolan R, Putananickal N, Tritten L, Bouchery T. How to train your myeloid cells: a way forward for helminth vaccines? Front Immunol 2023; 14:1163364. [PMID: 37325618 PMCID: PMC10266106 DOI: 10.3389/fimmu.2023.1163364] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/25/2023] [Indexed: 06/17/2023] Open
Abstract
Soil-transmitted helminths affect approximately 1.5 billion people worldwide. However, as no vaccine is currently available for humans, the current strategy for elimination as a public health problem relies on preventive chemotherapy. Despite more than 20 years of intense research effort, the development of human helminth vaccines (HHVs) has not yet come to fruition. Current vaccine development focuses on peptide antigens that trigger strong humoral immunity, with the goal of generating neutralizing antibodies against key parasite molecules. Notably, this approach aims to reduce the pathology of infection, not worm burden, with only partial protection observed in laboratory models. In addition to the typical translational hurdles that vaccines struggle to overcome, HHVs face several challenges (1): helminth infections have been associated with poor vaccine responses in endemic countries, probably due to the strong immunomodulation caused by these parasites, and (2) the target population displays pre-existing type 2 immune responses to helminth products, increasing the likelihood of adverse events such as allergy or anaphylaxis. We argue that such traditional vaccines are unlikely to be successful on their own and that, based on laboratory models, mucosal and cellular-based vaccines could be a way to move forward in the fight against helminth infection. Here, we review the evidence for the role of innate immune cells, specifically the myeloid compartment, in controlling helminth infections. We explore how the parasite may reprogram myeloid cells to avoid killing, notably using excretory/secretory (ES) proteins and extracellular vesicles (EVs). Finally, learning from the field of tuberculosis, we will discuss how anti-helminth innate memory could be harnessed in a mucosal-trained immunity-based vaccine.
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Affiliation(s)
- Rory Doolan
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Namitha Putananickal
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Lucienne Tritten
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
- Institute of Parasitology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Tiffany Bouchery
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
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Chakraborty P, Aravindhan V, Mukherjee S. Helminth-derived biomacromolecules as therapeutic agents for treating inflammatory and infectious diseases: What lessons do we get from recent findings? Int J Biol Macromol 2023; 241:124649. [PMID: 37119907 DOI: 10.1016/j.ijbiomac.2023.124649] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023]
Abstract
Despite the tremendous progress in healthcare sectors, a number of life-threatening infectious, inflammatory, and autoimmune diseases are continuously challenging mankind throughout the globe. In this context, recent successes in utilizing helminth parasite-derived bioactive macromolecules viz. glycoproteins, enzymes, polysaccharides, lipids/lipoproteins, nucleic acids/nucleotides, and small organic molecules for treating various disorders primarily resulted from inflammation. Among the several parasites that infect humans, helminths (cestodes, nematodes, and trematodes) are known as efficient immune manipulators owing to their explicit ability to modulate and modify the innate and adaptive immune responses of humans. These molecules selectively bind to immune receptors on innate and adaptive immune cells and trigger multiple signaling pathways to elicit anti-inflammatory cytokines, expansion of alternatively activated macrophages, T-helper 2, and immunoregulatory T regulatory cell types to induce an anti-inflammatory milieu. Reduction of pro-inflammatory responses and repair of tissue damage by these anti-inflammatory mediators have been exploited for treating a number of autoimmune, allergic, and metabolic diseases. Herein, the potential and promises of different helminths/helminth-derived products as therapeutic agents in ameliorating immunopathology of different human diseases and their mechanistic insights of function at cell and molecular level alongside the molecular signaling cross-talks have been reviewed by incorporating up-to-date findings achieved in the field.
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Affiliation(s)
- Pritha Chakraborty
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol 713340, India
| | | | - Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol 713340, India.
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20
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Qiu H, Wang R, Xing J, Li L, Gao Z, Li J, Fang C, Shi F, Mo F, Liu L, Zhao Y, Xie H, Zhao S, Huang J. Characteristics of Th9 cells in Schistosoma japonicum-infected C57BL/6 mouse mesenteric lymph node. Mol Biochem Parasitol 2023; 254:111561. [PMID: 37086898 DOI: 10.1016/j.molbiopara.2023.111561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 04/24/2023]
Abstract
Interleukin 9 (IL-9) is an effective cytokine secreted by newly defined Th9 cells, which is involved in allergic and infectious diseases. In this study, lymphocytes were isolated from mesenteric lymph node (MLN), spleen, liver, lung, and Peyer's patches (PP) of C57BL/6 mice 5-6 weeks after S. japonicum infection, intracellular cytokine staining was done to detect the percentage of IL-9-producing CD4+ T cells. The qPCR and ELISA were used to verify the content of IL-9 in MLN. The population of IL-9-producing lymphocyte subset was identified by FACS. In addition, the dynamic changes and cytokine profiles of Th9 cells in the MLN of infected mice were detected by FACS. ELISA was used to detect IL-9 induced by soluble egg antigen (SEA) from isolated lymphocytes in mouse MLN. The results showed that the percentage of IL-9-secreting Th9 cells in the MLN of the infected mouse was higher than that in the spleen, liver, lung, or PP. Though CD8+ Tc cells, NKT cells, and γδT cells could secrete IL-9, CD4+ Th cells were the main source of IL-9 in S. japonicum-infected C57BL/6 mice (P < 0.05). The percentage of Th9 cells in MLN of infected mouse increased from week 3-4, and reached a peak at week 5-6, then began to decrease from week 7-8 (P < 0.05). Moreover, Th9 cells could also secrete a small amount of IL-4, IFN-γ, IL-5, and IL-10. Our results suggested a higher percentage of Th9 cells was induced in the MLN of S. japonicum-infected mice, which might play an important role in the early stage of S. japonicum-induced disease.
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Affiliation(s)
- Huaina Qiu
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Ruohan Wang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Junmin Xing
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Lu Li
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Zhiyan Gao
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Jiajie Li
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Chao Fang
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Feihu Shi
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Feng Mo
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Lin Liu
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Yi Zhao
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
| | - Hongyan Xie
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China.
| | - Shan Zhao
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China.
| | - Jun Huang
- China Sino-French Hoffmann Institute, Department of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China.
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21
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You H, Jones MK, Gordon CA, Arganda AE, Cai P, Al-Wassiti H, Pouton CW, McManus DP. The mRNA Vaccine Technology Era and the Future Control of Parasitic Infections. Clin Microbiol Rev 2023; 36:e0024121. [PMID: 36625671 PMCID: PMC10035331 DOI: 10.1128/cmr.00241-21] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Despite intensive long-term efforts, with very few exceptions, the development of effective vaccines against parasitic infections has presented considerable challenges, given the complexity of parasite life cycles, the interplay between parasites and their hosts, and their capacity to escape the host immune system and to regulate host immune responses. For many parasitic diseases, conventional vaccine platforms have generally proven ill suited, considering the complex manufacturing processes involved and the costs they incur, the inability to posttranslationally modify cloned target antigens, and the absence of long-lasting protective immunity induced by these antigens. An effective antiparasite vaccine platform is required to assess the effectiveness of novel vaccine candidates at high throughput. By exploiting the approach that has recently been used successfully to produce highly protective COVID mRNA vaccines, we anticipate a new wave of research to advance the use of mRNA vaccines to prevent parasitic infections in the near future. This article considers the characteristics that are required to develop a potent antiparasite vaccine and provides a conceptual foundation to promote the development of parasite mRNA-based vaccines. We review the recent advances and challenges encountered in developing antiparasite vaccines and evaluate the potential of developing mRNA vaccines against parasites, including those causing diseases such as malaria and schistosomiasis, against which vaccines are currently suboptimal or not yet available.
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Affiliation(s)
- Hong You
- Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Malcolm K. Jones
- School of Veterinary Science, The University of Queensland, Brisbane, Australia
| | - Catherine A. Gordon
- Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Alexa E. Arganda
- Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Pengfei Cai
- Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Harry Al-Wassiti
- Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Colin W. Pouton
- Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Donald P. McManus
- Department of Infection and Inflammation, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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22
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Ullah H, Tian Y, Arbab S, Li K, Khan MIU, Rahman SU, Qadeer A, Muhammad N, Suleman, Hassan IU. Circulatory microRNAs in helminthiases: Potent as diagnostics biomarker, its potential role and limitations. Front Vet Sci 2022; 9:1018872. [PMID: 36387413 PMCID: PMC9650547 DOI: 10.3389/fvets.2022.1018872] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 09/30/2022] [Indexed: 08/08/2023] Open
Abstract
Infections caused by helminths are responsible for severe public health problems and economic burden on continental scale. Well-timed and precise diagnosis of helminth infections is critical for taking by appropriate approaches for pathogen control. Circulating miRNAs are stable diagnostic tool for different diseases found in a variety of body fluid. As diagnostic biomarkers in infectious diseases, miRNAs detection in body fluids of helminth infected hosts is growing promptly. Uncovering miRNAs is a relatively new tool, used for early-stage detection of helminth infection from experimental or non-invasive clinical samples. miRNAs can be detected in body fluids such as serum, saliva, urine, and tissues of helminth infected host, mainly blood offering important benefits for diagnosis accurately. In this review, we discuss different characteristics of helminth parasite-derived circulating and EV miRNAs, supporting its potential uses in for helminth diagnosis and treatment efficiency.
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Affiliation(s)
- Hanif Ullah
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China
| | - Yali Tian
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China
| | - Safia Arbab
- Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Key Laboratory of New Animal Drug Project of Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Ka Li
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China
| | - Muhammad Inayat Ullah Khan
- State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Wuhan, China
| | - Sajid Ur Rahman
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Abdul Qadeer
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Nehaz Muhammad
- Department of Zoology, University of Swabi, Swabi, Pakistan
| | - Suleman
- Department of Zoology, University of Swabi, Swabi, Pakistan
| | - Inam Ul Hassan
- Department of Microbiology, Hazara University Manshera, Manshera, Pakistan
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Guo X, Wang S, Zhang J, Li R, Zhang Y, Wang Z, Kong Q, Cho WC, Ju X, Shen Y, Zhang L, Fan H, Cao J, Zheng Y. Proteomic profiling of serum extracellular vesicles identifies diagnostic markers for echinococcosis. PLoS Negl Trop Dis 2022; 16:e0010814. [PMID: 36206314 PMCID: PMC9581430 DOI: 10.1371/journal.pntd.0010814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/19/2022] [Accepted: 09/14/2022] [Indexed: 11/06/2022] Open
Abstract
Echinococcosis is a parasitic disease caused by the metacestodes of Echinococcus spp. The disease has a long latent period and is largely underdiagnosed, partially because of the lack of effective early diagnostic approaches. Using liquid chromatography-mass spectrometry, we profiled the serum-derived extracellular vesicles (EVs) of E. multilocularis-infected mice and identified three parasite-origin proteins, thioredoxin peroxidase 1 (TPx-1), transitional endoplasmic reticulum ATPase (TER ATPase), and 14-3-3, being continuously released by the parasites into the sera during the infection via EVs. Using ELISA, both TPx-1 and TER ATPase were shown to have a good performance in diagnosis of experimental murine echinococcosis as early as 10 days post infection and of human echinococcosis compared with that of control. Moreover, TER ATPase and TPx-1 were further demonstrated to be suitable for evaluation of the prognosis of patients with treatment. The present study discovers the potential of TER ATPase and TPx-1 as promising diagnostic candidates for echinococcosis.
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Affiliation(s)
- Xiaola Guo
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Shuai Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Junmei Zhang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Rui Li
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Yong’e Zhang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Zhengrong Wang
- State Key Laboratory for Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Science, Shihezi, China
| | - Qingming Kong
- Institute of Parasitic Diseases, School of Biological Engineering, Hangzhou Medical College, Hangzhou, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Xianghong Ju
- Department of Veterinary Medicine, College of Agriculture, Guangdong Ocean University, Zhanjiang, China
| | - Yujuan Shen
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, (Chinese Center for Tropical Diseases Research), Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China; Shanghai, China
| | - Lingqiang Zhang
- Department of Hepatopancreatobiliary Surgery, Qinghai University Affiliated Hospital, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, Qinghai University Affiliated Hospital, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Jianping Cao
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, (Chinese Center for Tropical Diseases Research), Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China; Shanghai, China
| | - Yadong Zheng
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, China
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24
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Abou-El-Naga IF. Emerging roles for extracellular vesicles in Schistosoma infection. Acta Trop 2022; 232:106467. [PMID: 35427535 DOI: 10.1016/j.actatropica.2022.106467] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/05/2022] [Accepted: 04/11/2022] [Indexed: 11/01/2022]
Abstract
The co-evolution of Schistosoma and its host necessitates the use of extracellular vesicles (EVs) generated by different lifecycle stages to manipulate the host immune system to achieve a delicate balance between the survival of the parasite and the limited pathology of the host. EVs are phospholipid bilayer membrane-enclosed vesicles capable of transferring a complex mixture of proteins, lipids, and genetic materials to the host. They are nano-scale-sized vesicles involved in cellular communication. In this review, the author summarized the proteins involved in the biogenesis of schistosome-derived EVs and their cargo load. miRNAs are one cargo molecule that can underpin EVs functions and significantly affect parasite/host interactions and immune modulation. They skew macrophage polarization towards the M1 phenotype and downregulate Th2 immunity. Schistosoma can evade the host immune system's harmful effects by utilizing this strategy. In order to compromise the protective effect of Th2, EVs upregulate T regulatory cells and activate eosinophils, which contribute to granuloma formation. Schistosomal EVs also affect fibrosis by acting on non-immune cells such as hepatic stellate cells. These vesicles drew attention to translational applications in diagnosis, immunotherapy, and potential vaccines. A deep understanding of the interaction of schistosome-derived EVs with host cells will significantly increase our knowledge about the dynamics between the host and the worm that may aid in controlling this debilitating disease.
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25
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Bioinformatics analysis and experimental verification of Notch signalling pathway-related miRNA-mRNA subnetwork in extracellular vesicles during Echinococcus granulosus encystation. Parasit Vectors 2022; 15:272. [PMID: 35906657 PMCID: PMC9338502 DOI: 10.1186/s13071-022-05391-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/05/2022] [Indexed: 12/02/2022] Open
Abstract
Background Encystation of the protoscoleces (PSCs) of Echinococcus granulosus is the main cause of secondary hydatid dissemination in the intermediate host. Extracellular vesicles (EVs) can transfer miRNAs into parasite cells to regulate mRNA expression. However, loading of developmental pathway-related miRNAs, such as those related to the Notch signalling pathway in EVs is unclear. Thus, we screened the miRNA-mRNA subnetwork involved in the Notch pathway during E. granulosus encystation in vitro and assessed changes in expression in the parasite and EVs. Methods mRNAs and miRNAs differentially expressed (DE) between PSCs and microcysts (MCs) were screened using high-throughput sequencing. DE mRNAs obtained from transcriptome analysis were intersected with mRNAs predicted to be targets of the conserved DE miRNAs of a small RNA library. DE miRNA functions were analysed using public databases, and a miRNA–mRNA subnetwork related to the Notch pathway was established. Notch pathway-related mRNA and miRNA expression of worms and EVs at different times was verified. Results In total, 1445 DE mRNAs between MCs and PSCs were screened after the intersection between 1586 DE mRNAs from the transcriptome and 9439 target mRNAs predicted using 39 DE miRNAs from the small RNA library. The DE mRNAs were clustered into 94 metabolic pathways, including the Notch pathway. Five DE miRNAs, including the most significantly expressed new DE miRNA, egr-new-mir0694-3p, corresponding to four target mRNAs (EgrG_000892700, EgrG_001029400, EgrG_001081400 and EgrG_000465800) were all enriched in the Notch pathway. The expression of the above mRNAs and miRNAs was consistent with the results of high-throughput sequencing, and the expression of each miRNA in EVs was verified. Annotated as ADAM17/TACE in the Notch pathway, EgrG_000892700 was down-regulated during PSC encystation. egr-miR-4989-3p and egr-miR-277a-3p expression in EVs after encystation was nearly five times that in EVs before encystation, which might regulate the expression of EgrG_000892700. Conclusions Five miRNAs corresponding to four target mRNAs may be involved in regulating the Notch pathway during the PSC encystation. EVs may regulate the expression of EgrG_000892700 in PSCs because of continuous targeting of egr-miR-4989-3p and egr-miR-277a-3p and participate in the regulation the Notch pathway. The study might expand new ideas for blocking the secondary infection of E. granulosus PSCs via EVs miRNAs. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-022-05391-8.
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Zhang X, Duan S, Li X, Ding J, Zuo L, Sun B, Zhang X, Jiang X, Gao Y, Hu X, Han S. Differences in the secretory exosomes of Clonorchis sinensis adults at different incubation times. Acta Trop 2022; 234:106604. [PMID: 35820469 DOI: 10.1016/j.actatropica.2022.106604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/16/2022] [Accepted: 07/08/2022] [Indexed: 11/26/2022]
Abstract
Exosomes are small membrane vesicles of endocytic origin and widely involved in a variety of physiological and pathological conditions. Exosome-like vesicles (ELVs) have been identified to mediate the parasite-host interactions and communication. Thus, increased knowledge of C. sinensis ELVs could provide insights into parasite-host interactions. In this experiment, ELVs was purified by ultracentrifugation from the culture medium of C. sinensis adults in vitro incubated for 24 h and 48 h, respectively. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) confirmed that the purified vesicles which ranged from 30 to 150 nm in size were present in the culture medium. Small RNA high-throughput sequencing analysis identified 51 miRNAs, including 37 known C. sinensis miRNAs, 3 novel C. sinensis miRNAs and 11 rat miRNAs. The sequencing data were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The biological function of targets of known C. sinensis miRNAs were proved to associated with signal transduction, infectious diseases and the immune system. Further, 15 miRNAs were classified as differentially expressed in the 24h-ELVs compared to the 48h-ELVs. We found that the numbers and expression levels of most miRNAs from 24h-ELVs were more and higer than 48h-ELVs'. Our work provides important data for understanding the molecular mechanisms underlying the pathogenesis of C. sinensis adults ELVs.
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Affiliation(s)
- Xiaoli Zhang
- Department of Parasitology, Harbin Medical University, Harbin, PR China
| | - Shanshan Duan
- Department of Parasitology, Harbin Medical University, Harbin, PR China.
| | - Xiang Li
- Department of Parasitology, Harbin Medical University, Harbin, PR China
| | - Jian Ding
- Department of Parasitology, Harbin Medical University, Harbin, PR China
| | - Lijiao Zuo
- Department of Parasitology, Harbin Medical University, Harbin, PR China.
| | - Beibei Sun
- Zhuhai Maternal and Child Health Hospital, Guangdong, PR China.
| | - Xueli Zhang
- Department of Parasitology, Harbin Medical University, Harbin, PR China
| | - Xu Jiang
- Department of Parasitology, Harbin Medical University, Harbin, PR China
| | - Yannan Gao
- Department of Graduate Studies, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, PR China.
| | - Xinyi Hu
- Department of Stomatology, Laixi People's Hospital, Shandong, PR China
| | - Su Han
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China; Department of Parasitology, Harbin Medical University, Harbin, PR China.
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Extracellular Vesicles from Naegleria fowleri Induce IL-8 Response in THP-1 Macrophage. Pathogens 2022; 11:pathogens11060632. [PMID: 35745486 PMCID: PMC9231210 DOI: 10.3390/pathogens11060632] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/26/2022] [Accepted: 05/28/2022] [Indexed: 11/17/2022] Open
Abstract
Extracellular vesicles (EVs) released from pathogenic protozoans play crucial roles in host–parasite communication and disease pathogenesis. Naegleria fowleri is a free-living protozoan causing primary amoebic meningoencephalitis, a fatal disease in the central nervous system. This study aims to explore the roles of N. fowleri-derived EVs (Nf-EVs) in host–pathogen interactions using the THP-1 cell line as a model. The Nf-EVs were isolated from the N. fowleri trophozoite culture supernatant using sequential centrifugation and characterized by nanoparticle tracking analysis and transmission electron microscopy. The functional roles of Nf-EVs in the apoptosis and immune response induction of THP-1 monocytes and macrophages were examined by flow cytometry, quantitative PCR, and ELISA. Results showed that Nf-EVs displayed vesicles with bilayer membrane structure approximately 130–170 nm in diameter. The Nf-EVs can be internalized by macrophages and induce macrophage responses by induction of the expression of costimulatory molecules CD80, CD86, HLA-DR, and CD169 and the production of cytokine IL-8. However, Nf-EVs did not affect the apoptosis of macrophages. These findings illustrate the potential role of Nf-EVs in mediating the host immune cell activation and disease pathogenesis.
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Dagenais M, Gerlach JQ, Geary TG, Long T. Sugar Coating: Utilisation of Host Serum Sialoglycoproteins by Schistosoma mansoni as a Potential Immune Evasion Mechanism. Pathogens 2022; 11:pathogens11040426. [PMID: 35456101 PMCID: PMC9030049 DOI: 10.3390/pathogens11040426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/26/2022] [Accepted: 03/30/2022] [Indexed: 11/21/2022] Open
Abstract
Parasitic helminths resort to various mechanisms to evade and modulate their host’s immune response, several of which have been described for Schistosoma mansoni. We recently reported the presence of sialic acid residues on the surface of adult S. mansoni extracellular vesicles (EVs). We now report that these sialylated molecules are mammalian serum proteins. In addition, our data suggest that most sialylated EV-associated proteins do not elicit a humoral response upon injection into mice, or in sera obtained from infected animals. Sialic acids frequently terminate glycans on the surface of vertebrate cells, where they serve important functions in physiological processes such as cell adhesion and signalling. Interestingly, several pathogens have evolved ways to mimic or utilise host sialic acid beneficially by coating their own proteins, thereby facilitating cell invasion and providing protection from host immune effectors. Together, our results indicate that S. mansoni EVs are coated with host glycoproteins, which may contribute to immune evasion by masking antigenic sites, protecting EVs from removal from serum and aiding in cell adhesion and entry to exert their functions.
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Affiliation(s)
- Maude Dagenais
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada; (T.G.G.); (T.L.)
- Correspondence:
| | - Jared Q. Gerlach
- Advanced Glycoscience Research Cluster, National University of Ireland-Galway, H91 TK33 Galway, Ireland;
| | - Timothy G. Geary
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada; (T.G.G.); (T.L.)
- Microbes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University-Belfast, Belfast BT9 5DL, UK
| | - Thavy Long
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada; (T.G.G.); (T.L.)
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Jiang P, Wang J, Zhu S, Hu C, Lin Y, Pan W. Identification of a Schistosoma japonicum MicroRNA That Suppresses Hepatoma Cell Growth and Migration by Targeting Host FZD4 Gene. Front Cell Infect Microbiol 2022; 12:786543. [PMID: 35174106 PMCID: PMC8842725 DOI: 10.3389/fcimb.2022.786543] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 01/10/2022] [Indexed: 12/25/2022] Open
Abstract
Previous studies have demonstrated miRNAs derived from plants and parasites can modulate mammalian gene expression and cell phenotype in a cross-kingdom manner, leading to occurrence of diseases or strengthening resistance of host to diseases such as cancer. In this study, we identified a schistosome miRNA (named Sja-miR-71a) through screening of 57 Schistosoma japonicum miRNAs that exerts antitumor activity in vitro and in vivo models. We demonstrated presence of this parasite miRNA in liver cells during infection. We showed that Sja-miR-71a arrested cell cycle at G0/G1 phase of hepatoma cell lines and inhibited cell proliferation in vitro. The HepG2 transfected with Sja-miR-71a mimics displayed significant reduction of migration and colony formation. Further, growth of the tumor cells transfected with the Sja-miR-71a mimics was obviously suppressed in a xenograft mouse model. Mechanically, we found the antitumor activity of Sja-miR-71a was through targeting a host gene encoding Frizzled Class Receptor 4 (FZD4), as FZD4 small interfering RNAs (siRNAs) generated a similar inhibitory effect on the tumor. These data indicated that Sja-miR-71a is a tumor suppressor miRNA and suggested this parasite-derived miRNA as a potential therapeutic target for cancer.
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Affiliation(s)
- Pengyue Jiang
- Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China
| | - Jing Wang
- Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China
| | - Shanli Zhu
- Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China
| | - Chao Hu
- Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China
| | - Yu Lin
- Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China
| | - Weiqing Pan
- Institute for Infectious Diseases and Vaccine Development, Tongji University School of Medicine, Shanghai, China
- Department of Tropical Diseases, Naval Medical University, Shanghai, China
- *Correspondence: Weiqing Pan,
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Kumagai T, Shimogawara R, Ichimura K, Iwanaga S. Calpain inhibitor suppresses both extracellular vesicle-mediated secretion of miRNAs and egg production from paired adults of Schistosoma japonicum. Parasitol Int 2022; 87:102540. [PMID: 35007765 DOI: 10.1016/j.parint.2022.102540] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 01/08/2023]
Abstract
Extracellular vesicles (EVs) have been reported to be secreted from Schistosoma japonicum at all developmental stages. However, the reproduction and communication mechanisms between the paired adults through the EVs in dioecious Trematoda have not been reported. In this study, EVs containing many exosome-like vesicles and microvesicles were observed in the supernatants of paired adults cultured in vitro, and abundant selected miRNAs were contained in them. In particular, the female-specific miR-bantam was present only in vesicles and was hardly secreted outside the vesicles. In this study, we found that male-female pairing induced secretion of miR-3479 and miR-bantam in EVs, but not of male-specific miR-61. Furthermore, ingestion of mouse erythrocytes also increased the production of miRNAs in paired adult and single female worms. Vesicles were found in the tegument of females treated with erythrocytes under electron microscopy. After the paired worms were treated with several inhibitors against the secretion of EVs, only calpain inhibitor (calpeptin) significantly reduced the amount of miRNA in EVs. Furthermore, the worms treated with only calpeptin inhibited egg production in vitro. Together, these results indicate that qualitative miRNA production through EVs regulated by calpain plays a role in egg production in S. japonicum.
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Affiliation(s)
- Takashi Kumagai
- Department of Parasitology and Tropical Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
| | - Rieko Shimogawara
- Department of Parasitology and Tropical Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Koichiro Ichimura
- Department of Anatomy and Life Structure, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Shiroh Iwanaga
- Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
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Abstract
Schistosomes are long lived, intravascular parasitic platyhelminths that infect >200 million people globally. The molecular mechanisms used by these blood flukes to dampen host immune responses are described in this review. Adult worms express a collection of host-interactive tegumental ectoenzymes that can cleave host signaling molecules such as the "alarmin" ATP (cleaved by SmATPDase1), the platelet activator ADP (SmATPDase1, SmNPP5), and can convert AMP into the anti-inflammatory mediator adenosine (SmAP). SmAP can additionally cleave the lipid immunomodulator sphingosine-1-phosphate and the proinflammatory anionic polymer, polyP. In addition, the worms release a barrage of proteins (e.g., SmCB1, SjHSP70, cyclophilin A) that can impinge on immune cell function. Parasite eggs also release their own immunoregulatory proteins (e.g., IPSE/α1, omega1, SmCKBP) as do invasive cercariae (e.g., Sm16, Sj16). Some schistosome glycans (e.g., LNFPIII, LNnT) and lipids (e.g., Lyso-PS, LPC), produced by several life stages, likewise affect immune cell responses. The parasites not only produce eicosanoids (e.g., PGE2, PGD2-that can be anti-inflammatory) but can also induce host cells to release these metabolites. Finally, the worms release extracellular vesicles (EVs) containing microRNAs, and these too have been shown to skew host cell metabolism. Thus, schistosomes employ an array of biomolecules-protein, lipid, glycan, nucleic acid, and more, to bend host biochemistry to their liking. Many of the listed molecules have been individually shown capable of inducing aspects of the polarized Th2 response seen following infection (with the generation of regulatory T cells (Tregs), regulatory B cells (Bregs) and anti-inflammatory, alternatively activated (M2) macrophages). Precisely how host cells integrate the impact of these myriad parasite products following natural infection is not known. Several of the schistosome immunomodulators described here are in development as novel therapeutics against autoimmune, inflammatory, and other, nonparasitic, diseases.
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Affiliation(s)
- Sreemoyee Acharya
- Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, United States of America
| | - Akram A. Da’dara
- Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, United States of America
| | - Patrick J. Skelly
- Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, United States of America
- * E-mail:
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Lechner A, Bohnacker S, Esser-von Bieren J. Macrophage regulation & function in helminth infection. Semin Immunol 2021; 53:101526. [PMID: 34802871 DOI: 10.1016/j.smim.2021.101526] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 11/03/2021] [Accepted: 11/06/2021] [Indexed: 12/14/2022]
Abstract
Macrophages are innate immune cells with essential roles in host defense, inflammation, immune regulation and repair. During infection with multicellular helminth parasites, macrophages contribute to pathogen trapping and killing as well as to tissue repair and the resolution of type 2 inflammation. Macrophages produce a broad repertoire of effector molecules, including enzymes, cytokines, chemokines and growth factors that govern anti-helminth immunity and repair of parasite-induced tissue damage. Helminth infection and the associated type 2 immune response induces an alternatively activated macrophage (AAM) phenotype that - beyond driving host defense - prevents aberrant Th2 cell activation and type 2 immunopathology. The immune regulatory potential of macrophages is exploited by helminth parasites that induce the production of anti-inflammatory mediators such as interleukin 10 or prostaglandin E2 to evade host immunity. Here, we summarize current insights into the mechanisms of macrophage-mediated host defense and repair during helminth infection and highlight recent progress on the immune regulatory crosstalk between macrophages and helminth parasites. We also point out important remaining questions such as the translation of findings from murine models to human settings of helminth infection as well as long-term consequences of helminth-induced macrophage reprogramming for subsequent host immunity.
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Affiliation(s)
- Antonie Lechner
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802, Munich, Germany
| | - Sina Bohnacker
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802, Munich, Germany
| | - Julia Esser-von Bieren
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802, Munich, Germany.
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Csi-let-7a-5p delivered by extracellular vesicles from a liver fluke activates M1-like macrophages and exacerbates biliary injuries. Proc Natl Acad Sci U S A 2021; 118:2102206118. [PMID: 34772807 DOI: 10.1073/pnas.2102206118] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic infection with liver flukes (such as Clonorchis sinensis) can induce severe biliary injuries, which can cause cholangitis, biliary fibrosis, and even cholangiocarcinoma. The release of extracellular vesicles by C. sinensis (CsEVs) is of importance in the long-distance communication between the hosts and worms. However, the biological effects of EVs from liver fluke on biliary injuries and the underlying molecular mechanisms remain poorly characterized. In the present study, we found that CsEVs induced M1-like activation. In addition, the mice that were administrated with CsEVs showed severe biliary injuries associated with remarkable activation of M1-like macrophages. We further characterized the signatures of miRNAs packaged in CsEVs and identified a miRNA Csi-let-7a-5p, which was highly enriched. Further study showed that Csi-let-7a-5p facilitated the activation of M1-like macrophages by targeting Socs1 and Clec7a; however, CsEVs with silencing Csi-let-7a-5p showed a decrease in proinflammatory responses and biliary injuries, which involved in the Socs1- and Clec7a-regulated NF-κB signaling pathway. Our study demonstrates that Csi-let-7a-5p delivered by CsEVs plays a critical role in the activation of M1-like macrophages and contributes to the biliary injuries by targeting the Socs1- and Clec7a-mediated NF-κB signaling pathway, which indicates a mechanism contributing to biliary injuries caused by fluke infection. However, molecules other than Csi-let-7a-5p from CsEVs that may also promote M1-like polarization and exacerbate biliary injuries are not excluded.
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Mammes A, Pasquier J, Mammes O, Conti M, Douard R, Loric S. Extracellular vesicles: General features and usefulness in diagnosis and therapeutic management of colorectal cancer. World J Gastrointest Oncol 2021; 13:1561-1598. [PMID: 34853637 PMCID: PMC8603448 DOI: 10.4251/wjgo.v13.i11.1561] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/29/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
In the world, among all type of cancers, colorectal cancer (CRC) is the third most commonly diagnosed in males and the second in females. In most of cases, (RP1) patients’ prognosis limitation with malignant tumors can be attributed to delayed diagnosis of the disease. Identification of patients with early-stage disease leads to more effective therapeutic interventions. Therefore, new screening methods and further innovative treatment approaches are mandatory as they may lead to an increase in progression-free and overall survival rates. For the last decade, the interest in extracellular vesicles (EVs) research has exponentially increased as EVs generation appears to be a universal feature of every cell that is strongly involved in many mechanisms of cell-cell communication either in physiological or pathological situations. EVs can cargo biomolecules, such as lipids, proteins, nucleic acids and generate transmission signal through the intercellular transfer of their content. By this mechanism, tumor cells can recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. This review intends to cover the most recent literature on the role of EVs production in colorectal normal and cancer tissues. Specific attention is paid to the use of EVs for early CRC diagnosis, follow-up, and prognosis as EVs have come into the spotlight of research as a high potential source of ‘liquid biopsies’. The use of EVs as new targets or nanovectors as drug delivery systems for CRC therapy is also summarized.
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Affiliation(s)
- Aurelien Mammes
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
| | - Jennifer Pasquier
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
| | | | - Marc Conti
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
- Metabolism Research Unit, Integracell SAS, Longjumeau 91160, France
| | - Richard Douard
- UCBM, Necker University Hospital, Paris 75015, France
- Gastrointestinal Surgery Department, Clinique Bizet, Paris 75016, France
| | - Sylvain Loric
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
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Guo A, Wang L, Meng X, Zhang S, Sheng Z, Luo X, Huang W, Wang S, Cai X. Extracellular vesicles from Fasciola gigantica induce cellular response to stress of host cells. Exp Parasitol 2021; 231:108173. [PMID: 34742714 DOI: 10.1016/j.exppara.2021.108173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 09/14/2021] [Accepted: 10/31/2021] [Indexed: 11/18/2022]
Abstract
Extracellular vesicles (EVs) from parasitic helminths play an important role in immunomodulation. However, EVs are little studied in the important parasite Fasciola gigantica. Here the ability of EVs from F. gigantica to induce cellular response to stress (reactive oxygen species generation, autophage and DNA damage response) in human intrahepatic biliary epithelial cells (HIBEC) was investigated. F. gigantica-derived EVs were isolated by ultracentrifugation, and identified with transmission electron microscopy, nanoparticle size analysis and parasite-derived EV markers. Internalization of EVs by HIBEC was determined by confocal immunofluorescence microscopy and flow cytometry. ROS levels in HIBEC were detected by molecular probing. EVs-induced autophagy and DNA-damaging effects were determined by evaluating expression levels of light chain 3B protein (LC3B), phosphor- H2A.X and phosphor-Chk1, respectively. Results revealed that EVs with sizes predominately ranging from 39 to 110 nm in diameter were abundant in adult F. gigantica and contained the parasite-derived marker proteins enolase and 14-3-3, and EVs were internalized by HIBEC. Further, uptake of EVs into HIBEC was associated with increased levels of reactive oxygen species, LC3Ⅱ, phosphor-H2A.X and phosphor-Chk1, suggesting EVs are likely to induce autophagy and DNA damage & repair processes. These results indicate F. gigantica EVs are associated with modulations of host cell responses and have a potential important role in the host-parasite interactions.
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Affiliation(s)
- Aijiang Guo
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu Province, China
| | - Li Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China; Shandong New Hope Liuhe Group Co., Ltd. Qingdao, China
| | - Xuelian Meng
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China
| | - Shaohua Zhang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China
| | - Zhaoan Sheng
- College of Animal Science and Technology, Guangxi University, Nanning, China
| | - Xuenong Luo
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu Province, China
| | - Weiyi Huang
- College of Animal Science and Technology, Guangxi University, Nanning, China
| | - Shuai Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China.
| | - Xuepeng Cai
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China.
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Dagenais M, Gerlach JQ, Wendt GR, Collins JJ, Atkinson LE, Mousley A, Geary TG, Long T. Analysis of Schistosoma mansoni Extracellular Vesicles Surface Glycans Reveals Potential Immune Evasion Mechanism and New Insights on Their Origins of Biogenesis. Pathogens 2021; 10:1401. [PMID: 34832557 PMCID: PMC8617790 DOI: 10.3390/pathogens10111401] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 12/26/2022] Open
Abstract
Parasitic helminths are master manipulators of host immunity. Their strategy is complex and involves the release of excreted/secreted products, including extracellular vesicles (EVs). The protein and miRNA contents of EVs have been characterised for many parasitic helminths but, despite reports suggesting the importance of EV surface carbohydrate structures (glycans) in the interactions with target cells and thus subsequent effector functions, little is known about parasite EV glycomics. Using lectin microarrays, we identified several lectins that exhibit strong adhesion to Schistosoma mansoni EVs, suggesting the presence of multiple glycan structures on these vesicles. Interestingly, SNA-I, a lectin that recognises structures with terminal sialic acid, displayed strong affinity for S. mansoni EVs, which was completely abolished by neuraminidase treatment, suggesting sialylation in the EV sample. This finding is of interest, as sialic acids play important roles in the context of infection by aiding immune evasion, affecting target recognition, cell entry, etc., but are not thought to be synthesised by helminths. These data were validated by quantitative analysis of free sialic acid released from EVs following treatment with neuraminidase. Lectin histochemistry and fluorescence in situ hybridisation analyses on whole adult worms suggest the involvement of sub-tegumental cell bodies, as well as the digestive and excretory systems, in the release of EVs. These results support previous reports of EV biogenesis diversity in trematodes and potentially highlight new means of immune modulation and evasion employed by schistosomes.
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Affiliation(s)
- Maude Dagenais
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada; (T.G.G.); (T.L.)
| | - Jared Q. Gerlach
- Glycoscience Group, Advanced Glycoscience Research Cluster, National Centre for Biomedical Engineering Science, National University of Ireland Galway, H91 TK33 Galway, Ireland;
| | - George R. Wendt
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (G.R.W.); (J.J.C.III)
| | - James J. Collins
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (G.R.W.); (J.J.C.III)
| | - Louise E. Atkinson
- Microbes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University-Belfast, Belfast BT9 5DL, UK; (L.E.A.); (A.M.)
| | - Angela Mousley
- Microbes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University-Belfast, Belfast BT9 5DL, UK; (L.E.A.); (A.M.)
| | - Timothy G. Geary
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada; (T.G.G.); (T.L.)
- Microbes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University-Belfast, Belfast BT9 5DL, UK; (L.E.A.); (A.M.)
| | - Thavy Long
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada; (T.G.G.); (T.L.)
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Schistosoma mansoni egg-derived extracellular vesicles: A promising vaccine candidate against murine schistosomiasis. PLoS Negl Trop Dis 2021; 15:e0009866. [PMID: 34644290 PMCID: PMC8544836 DOI: 10.1371/journal.pntd.0009866] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/25/2021] [Accepted: 09/30/2021] [Indexed: 02/05/2023] Open
Abstract
Extracellular vesicles (EVs) are protein-loaded nano-scaled particles that are extracellularly released by eukaryotes and prokaryotes. Parasite's EVs manipulate the immune system, making them probable next-generation vaccines. Schistosomal EVs carry different proteins of promising immunizing potentials. For evaluating the immune-protective role of Schistosoma mansoni (S. mansoni) egg-derived EVs against murine schistosomiasis, EVs were isolated from cultured S. mansoni eggs by progressive sequential cooling ultra-centrifugation technique. Isolated EVs were structurally identified using transmission electron microscope and their protein was quantified by Lowry's technique. Experimental mice were subcutaneously immunized with three doses of 20 μg EVs (with or without alum adjuvant); every two weeks, then were challenged with S. mansoni cercariae two weeks after the last immunizing dose. Six weeks post infection, mice were sacrificed for vaccine candidate assessment. EVs protective efficacy was evaluated through parasitological, histopathological, and immunological parameters. Results showed significant reduction of tegumentally deranged adult worms, hepatic and intestinal egg counts reduction by 46.58%, 93.14% and 93.17% respectively, accompanied by remarkable amelioration of sizes, numbers and histopathology of hepatic granulomata mediated by high interferon gamma (IFN γ) and antibody level. Using sera from vaccinated mice, the molecular weight of EVs' protein components targeted by the antibody produced was recognized by western immunoblot. Results revealed two bands of ~ 14 KDa and ~ 21 KDa, proving that EVs are able to stimulate specific antibodies response. In conclusion, the present study highlighted the role of S. mansoni-egg derived EVs as a potential vaccine candidate against murine schistosomiasis mansoni.
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Drurey C, Maizels RM. Helminth extracellular vesicles: Interactions with the host immune system. Mol Immunol 2021; 137:124-133. [PMID: 34246032 PMCID: PMC8636279 DOI: 10.1016/j.molimm.2021.06.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/14/2021] [Accepted: 06/23/2021] [Indexed: 12/21/2022]
Abstract
As long-lived parasites, helminths depend upon immunomodulation of their hosts for survival. The release of excretory-secretory (ES) products, including proteins, lipids and RNAs is how successful host manipulation is achieved. It has recently been discovered that the ES products of helminths contain extracellular vesicles (EVs), with every species investigated found to secrete these lipid-bound structures. EVs are perfect for packaging and delivering immune modulators to target cell types. This review outlines the research carried out on helminth EVs and their constituents thus far, as well as their interaction with components of the mammalian immune system. We discuss how targeting EVs will aid treatment of helminth infection and consider how EVs and their immunomodulatory cargo could be used as therapeutics as we progress through this exciting era.
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Affiliation(s)
- Claire Drurey
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
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Ilić N, Kosanović M, Gruden-Movsesijan A, Glamočlija S, Sofronić-Milosavljević L, Čolić M, Tomić S. Harnessing immunomodulatory mechanisms of Trichinella spiralis to design novel nanomedical approaches for restoring self-tolerance in autoimmunity. Immunol Lett 2021; 238:57-67. [PMID: 34363897 DOI: 10.1016/j.imlet.2021.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/28/2021] [Accepted: 04/28/2021] [Indexed: 01/13/2023]
Abstract
The rapid increase in the prevalence of autoimmune diseases in recent decades, especially in developed countries, coincided with improved living conditions and healthcare. Part of this increase could be ascribed to the lack of exposure to infectious agents like helminths that co-evolved with us and display potent immune regulatory actions. In this review we discussed many investigations, including our own, showing that Trichinella spiralis via its excretory-secretory products attenuate Th1/Th17 immunopathological response in autoimmunity and potentiate the protective Th2 and or regulatory T cell response, acting as an effective induction of tolerogenic dendritic cells (DCs), and probably mimicking the autoantigen in some diseases. A recent discovery of T. spiralis extracellular vesicles (TsEVs) suggested that inducing a complex regulation of the immune response requires simultaneous delivery of different signals in nano-sized packages. Indeed, different artificial nanomedical approaches discussed here suggested that co-delivery of multiple signals via nanoparticles is the most promising strategy for the treatment of autoimmune diseases. Although a long way is ahead of us before we could completely replicate natural nano-delivery systems which are both safe and potent in restoring self-tolerance, a clear path is being opened from a careful examination of parasite-host interactions.
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Affiliation(s)
- Nataša Ilić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia
| | - Maja Kosanović
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia
| | - Alisa Gruden-Movsesijan
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia
| | - Sofija Glamočlija
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia
| | - Ljiljana Sofronić-Milosavljević
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia
| | - Miodrag Čolić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia; Medical Faculty Foča, University of East Sarajevo, Bosnia and Hercegovina; Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Sergej Tomić
- Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University in Belgrade, Serbia.
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40
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Wan S, Sun X, Tang W, Wang L, Wu Z, Sun X. Exosome-Depleted Excretory-Secretory Products of the Fourth-Stage Larval Angiostrongylus cantonensis Promotes Alternative Activation of Macrophages Through Metabolic Reprogramming by the PI3K-Akt Pathway. Front Immunol 2021; 12:685984. [PMID: 34367145 PMCID: PMC8343011 DOI: 10.3389/fimmu.2021.685984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/07/2021] [Indexed: 12/19/2022] Open
Abstract
Angiostrongylus cantonensis (AC), which parasitizes in the brain of the non-permissive host, such as mouse and human, is an etiologic agent of eosinophilic meningitis. Excretory-secretory (ES) products play an important role in the interaction between parasites and hosts’ immune responses. Inflammatory macrophages are responsible for eosinophilic meningitis induced by AC, and the soluble antigens of Angiostrongylus cantonensis fourth stage larva (AC L4), a mimic of dead AC L4, aggravate eosinophilic meningitis in AC-infected mice model via promoting alternative activation of macrophages. In this study, we investigated the key molecules in the ES products of AC L4 on macrophages and observed the relationship between metabolic reprogramming and the PI3K-Akt pathway. First, a co-culture system of macrophage and AC L4 was established to define the role of AC L4 ES products on macrophage polarization. Then, AC L4 exosome and exosome-depleted excretory-secretory products (exofree) were separated from AC L4 ES products using differential centrifugation, and their distinct roles on macrophage polarization were confirmed using qPCR and ELISA experiments. Moreover, AC L4 exofree induced alternative activation of macrophages, which is partially associated with metabolic reprogramming by the PI3K-Akt pathway. Next, lectin blot and deglycosylation assay were done, suggesting the key role of N-linked glycoproteins in exofree. Then, glycoproteomic analysis of exofree and RNA-seq analysis of exofree-treated macrophage were performed. Bi-layer PPI network analysis based on these results identified macrophage-related protein Hexa as a key molecule in inducing alternative activation of macrophages. Our results indicate a great value for research of helminth-derived immunoregulatory molecules, which might contribute to drug development for immune-related diseases.
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Affiliation(s)
- Shuo Wan
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China.,The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Xiaoqiang Sun
- Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Zhongshan School of Mathematics, Sun Yat-Sen University, Guangzhou, China
| | - Wenyan Tang
- Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Lifu Wang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Zhongdao Wu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Xi Sun
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
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41
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Wang L, Liu T, Chen G, Li Y, Zhang S, Mao L, Liang P, Fasihi Harandi M, Li T, Luo X. Exosomal microRNA let-7-5p from Taenia pisiformis Cysticercus Prompted Macrophage to M2 Polarization through Inhibiting the Expression of C/EBP δ. Microorganisms 2021; 9:microorganisms9071403. [PMID: 34209741 PMCID: PMC8307393 DOI: 10.3390/microorganisms9071403] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 12/04/2022] Open
Abstract
Cysticercus pisiformis, the larval stage of Taenia pisiformis, causes serious illness in rabbits that severely impacts the rabbit breeding industry. An inhibitive Th2 immune response can be induced by let-7-enriched exosomes derived from T. pisiformis cysticercus. However, the underlying molecular mechanisms are not completely understood. Here, we report that exosomal miR-let-7-5p released by T. pisiformis cysticercus played a critical role in the activation of M2 macrophages. We found that overexpression of let-7-5p in M1 macrophages decreased M1 phenotype expression while promoting polarization to the M2 phenotype, which is consistent with experimental data in exosome-treated macrophages alone. In contrast, knockdown of let-7-5p in exosome-like vesicles promoted M1 polarization and decreased M2 phenotype expression. Furthermore, down-regulation of transcription factor CCAAT/enhancer-binding protein (C/EBP)-δ resulted in the decrease of M1 phenotype markers and increase of M2 phenotype markers. These results suggested that let-7 enriched in exosome-like vesicles from T. pisiformis metacestodes can induce M2 macrophage polarization via targeting C/EBP δ, which may be involved in macrophage polarization induced by T. pisiformis metacestodes. The finding helps to expand our knowledge of the molecular mechanism of immunosuppression and Th2 immune response induced by metacestodes.
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Affiliation(s)
- Liqun Wang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Tingli Liu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Guoliang Chen
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Yanping Li
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Shaohua Zhang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Li Mao
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Panhong Liang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Majid Fasihi Harandi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman 7616914115, Iran;
| | - Taoshan Li
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
| | - Xuenong Luo
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou 730046, China; (L.W.); (T.L.); (G.C.); (Y.L.); (S.Z.); (L.M.); (P.L.); (T.L.)
- Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou 225009, China
- Correspondence:
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42
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Yuan Y, Zhao J, Chen M, Liang H, Long X, Zhang B, Chen X, Chen Q. Understanding the Pathophysiology of Exosomes in Schistosomiasis: A New Direction for Disease Control and Prevention. Front Immunol 2021; 12:634138. [PMID: 34220800 PMCID: PMC8242937 DOI: 10.3389/fimmu.2021.634138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Schistosomiasis is a parasitic disease endemic to freshwater areas of Southeast Asia, Africa, and South America that is capable of causing serious damage to the internal organs. Recent studies have linked exosomes to the progression of schistosomiasis. These structures are important mediators for intercellular communication, assist cells to exchange proteins, lipids, and genetic material and have been shown to play critical roles during host-parasite interactions. This review aims to discuss the pathophysiology of exosomes in schistosomiasis and their roles in regulating the host immune response. Understanding how exosomes are involved in the pathogenesis of schistosomiasis may provide new perspectives in diagnosing and treating this neglected disease.
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Affiliation(s)
- Yue Yuan
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Jianping Zhao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Min Chen
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Xin Long
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
| | - Qian Chen
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
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43
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Luo M, Xu L, Qian Z, Sun X. Infection-Associated Thymic Atrophy. Front Immunol 2021; 12:652538. [PMID: 34113341 PMCID: PMC8186317 DOI: 10.3389/fimmu.2021.652538] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/07/2021] [Indexed: 12/17/2022] Open
Abstract
The thymus is a vital organ of the immune system that plays an essential role in thymocyte development and maturation. Thymic atrophy occurs with age (physiological thymic atrophy) or as a result of viral, bacterial, parasitic or fungal infection (pathological thymic atrophy). Thymic atrophy directly results in loss of thymocytes and/or destruction of the thymic architecture, and indirectly leads to a decrease in naïve T cells and limited T cell receptor diversity. Thus, it is important to recognize the causes and mechanisms that induce thymic atrophy. In this review, we highlight current progress in infection-associated pathogenic thymic atrophy and discuss its possible mechanisms. In addition, we discuss whether extracellular vesicles/exosomes could be potential carriers of pathogenic substances to the thymus, and potential drugs for the treatment of thymic atrophy. Having acknowledged that most current research is limited to serological aspects, we look forward to the possibility of extending future work regarding the impact of neural modulation on thymic atrophy.
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Affiliation(s)
- Mingli Luo
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Lingxin Xu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Zhengyu Qian
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Xi Sun
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
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44
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Transcriptional profiles of genes potentially involved in extracellular vesicle biogenesis in Schistosoma japonicum. Acta Trop 2021; 217:105851. [PMID: 33524382 DOI: 10.1016/j.actatropica.2021.105851] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 01/16/2021] [Accepted: 01/22/2021] [Indexed: 01/16/2023]
Abstract
Schistosomiasis is a severe chronic disease caused by parasitic worms of the genus Schistosoma. Recent studies indicate that schistosomes can secrete extracellular vesicles (EVs), which play important regulatory roles in many biological processes. However, the mechanisms underlying EV biogenesis in schistosomes are poorly understood. In this study, we performed bioinformatic analyses and identified several genes putatively involved in EV biogenesis in Schistosoma japonicum, which were then confirmed by PCR. Quantitative transcriptional profiles of the selected genes indicated that they were differentially expressed in male and female worms as well as in the different developmental stages of S. japonicum. Thus, the highest expression of VAMP3 was detected in cercariae, whereas that of ARF6 was detected in eggs. RAB11A and the Syntenin-encoding gene SDCBP were highly expressed in 14-day schistosomula and VPS4A and RAB27A were highly expressed in 35-day-old adult schistosomes. The expression of RAB11A, CHMP4C, VPS4A, and SDCBP was higher in male worms, whereas that of ARF6, VAMP3, and RAB27A was higher in female worms. Our results are expected to provide important clues for understanding the role of EV biogenesis in S. japonicum development.
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45
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Sánchez-López CM, Trelis M, Bernal D, Marcilla A. Overview of the interaction of helminth extracellular vesicles with the host and their potential functions and biological applications. Mol Immunol 2021; 134:228-235. [PMID: 33836351 DOI: 10.1016/j.molimm.2021.03.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/08/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023]
Abstract
Helminth Extracellular Vesicles (EVs) have emerged as important mediators in host-parasite communications, participating in the parasite survival and its pathogenic effects. In the last decade, a growing amount of information reporting the isolation and characterization of EVs from different helminth species has appeared, but unfortunately, few reports have focused on functional studies of helminth EVs in different cell lines, organoids or animal models. We here review these in vitro and in vivo studies, which clearly demonstrate that helminths secrete EVs, which affect their environment. Helminth EVs are actively internalized by different cell lines, modulating cellular functions important for host-parasite communication. We discuss how these lines of investigation should provide potential new biomarkers of infection, and since helminth EVs can modulate the host immune response, we also discuss how they can provide a new landscape for the development of new vaccine tools against helminthiases as well as immunotherapy.
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Affiliation(s)
- Christian M Sánchez-López
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Av. V.A. Estellés, s/n, 46100, Burjassot, Valencia, Spain; Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe-Universitat de València, 46026 Valencia, Spain
| | - María Trelis
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Av. V.A. Estellés, s/n, 46100, Burjassot, Valencia, Spain; Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe-Universitat de València, 46026 Valencia, Spain
| | - Dolores Bernal
- Departament de Bioquimica i Biologia Molecular, Facultat de Ciencies Biològiques, Universitat de València, C/ Dr. Moliner, 50, 46100 Burjassot, Valencia, Spain
| | - Antonio Marcilla
- Àrea de Parasitologia, Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia, Universitat de València, Av. V.A. Estellés, s/n, 46100, Burjassot, Valencia, Spain; Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe-Universitat de València, 46026 Valencia, Spain.
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Avni D, Avni O. Extracellular Vesicles: Schistosomal Long-Range Precise Weapon to Manipulate the Immune Response. Front Cell Infect Microbiol 2021; 11:649480. [PMID: 33869080 PMCID: PMC8044974 DOI: 10.3389/fcimb.2021.649480] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
Schistosomiasis (Bilharziasis), a neglected tropical disease that affects more than 240 million people around the world, is caused by infection with the helminth parasite Schistosoma. As part of their secretome, schistosomes release extracellular vesicles (EVs) that modulate the host immune response. The EV-harbored miRNAs upregulate the innate immune response of the M1 pathway and downregulate the differentiation toward the adaptive Th2 immunity. A schistosomal egg-derived miRNA increases the percentage of regulatory T cells. This schistosomal-inducible immunoediting process generates ultimately a parasitic friendly environment that is applied carefully as restrained Th2 response is crucial for the host survival and successful excretion of the eggs. Evidence indicates a selective targeting of schistosomal EVs, however, the underlying mechanisms are unclear yet. The effects of the schistosomes on the host immune system is in accordance with the hygiene hypothesis, attributing the dramatic increase in recent decades in allergy and other diseases associated with imbalanced immune response, to the reduced exposure to infectious agents that co-evolved with humans during evolution. Deciphering the bioactive cargo, function, and selective targeting of the parasite-secreted EVs may facilitate the development of novel tools for diagnostics and delivered therapy to schistosomiasis, as well as to immune-associated disorders.
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Affiliation(s)
- Dror Avni
- Laboratory of Molecular Cell Biology, Sheba Medical Center, Tel Hashomer, Israel.,Laboratory for the Study of Tropical Diseases, Sheba Medical Center, Tel Hashomer, Israel.,Department of Medicine C, Sheba Medical Center, Tel Hashomer, Israel
| | - Orly Avni
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
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47
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Hambrook JR, Hanington PC. Immune Evasion Strategies of Schistosomes. Front Immunol 2021; 11:624178. [PMID: 33613562 PMCID: PMC7889519 DOI: 10.3389/fimmu.2020.624178] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/22/2020] [Indexed: 11/13/2022] Open
Abstract
Human schistosomes combat the unique immune systems of two vastly different hosts during their indirect life cycles. In gastropod molluscs, they face a potent innate immune response composed of variable immune recognition molecules and highly phagocytic hemocytes. In humans, a wide variety of innate and adaptive immune processes exist in proximity to these parasites throughout their lifespan. To survive and thrive as the second most common parasitic disease in humans, schistosomes have evolved many techniques to avoid and combat these targeted host responses. Among these techniques are molecular mimicry of host antigens, the utilization of an immune resistant outer tegument, the secretion of several potent proteases, and targeted release of specific immunomodulatory factors affecting immune cell functions. This review seeks to describe these key immune evasion mechanisms, among others, which schistosomes use to survive in both of their hosts. After diving into foundational observational studies of the processes mediating the establishment of schistosome infections, more recent transcriptomic and proteomic studies revealing crucial components of the host/parasite molecular interface are discussed. In order to combat this debilitating and lethal disease, a comprehensive understanding of schistosome immune evasion strategies is necessary for the development of novel therapeutics and treatment plans, necessitating the discussion of the numerous ways in which these parasitic flatworms overcome the immune responses of both hosts.
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Affiliation(s)
- Jacob R Hambrook
- School of Public Health, University of Alberta, Edmonton, AB, Canada
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Layton E, Fairhurst AM, Griffiths-Jones S, Grencis RK, Roberts IS. Regulatory RNAs: A Universal Language for Inter-Domain Communication. Int J Mol Sci 2020; 21:E8919. [PMID: 33255483 PMCID: PMC7727864 DOI: 10.3390/ijms21238919] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
In eukaryotes, microRNAs (miRNAs) have roles in development, homeostasis, disease and the immune response. Recent work has shown that plant and mammalian miRNAs also mediate cross-kingdom and cross-domain communications. However, these studies remain controversial and are lacking critical mechanistic explanations. Bacteria do not produce miRNAs themselves, and therefore it is unclear how these eukaryotic RNA molecules could function in the bacterial recipient. In this review, we compare and contrast the biogenesis and functions of regulatory RNAs in eukaryotes and bacteria. As a result, we discovered several conserved features and homologous components in these distinct pathways. These findings enabled us to propose novel mechanisms to explain how eukaryotic miRNAs could function in bacteria. Further understanding in this area is necessary to validate the findings of existing studies and could facilitate the use of miRNAs as novel tools for the directed remodelling of the human microbiota.
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Affiliation(s)
- Emma Layton
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK; (E.L.); (S.G.-J.)
| | - Anna-Marie Fairhurst
- Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore;
| | - Sam Griffiths-Jones
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK; (E.L.); (S.G.-J.)
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Richard K. Grencis
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK; (E.L.); (S.G.-J.)
| | - Ian S. Roberts
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK; (E.L.); (S.G.-J.)
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Bischofsberger M, Winkelmann F, Rabes A, Reisinger EC, Sombetzki M. Pathogen-host interaction mediated by vesicle-based secretion in schistosomes. PROTOPLASMA 2020; 257:1277-1287. [PMID: 32462473 PMCID: PMC7449993 DOI: 10.1007/s00709-020-01515-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 05/15/2020] [Indexed: 05/07/2023]
Abstract
As part of the parasite's excretory/secretory system, extracellular vesicles (EVs) represent a potent communication tool of schistosomes with their human host to strike the balance between their own survival in a hostile immunological environment and a minimal damage to the host tissue. Their cargo consists of functional proteins, lipids, and nucleic acids that facilitate biological processes like migration, nutrient acquisition, or reproduction. The most important impact of the vesicle-mediated communication, however, is the promotion of the parasite survival via mimicking host protein function and directly or indirectly modulating the immune response of the host. Overcoming this shield of immunological adaption in the schistosome-host relation is the aim of current research activities in this field and crucial for the development of a reliable anti-schistosomal therapy. Not least because of their prospective use in clinical applications, research on EVs is now a rapidly expanding field. We herein focus on the current state of knowledge of vesicle-based communication of schistosomes and discussing the role of EVs in facilitating biological processes and immune modulatory properties of EVs considering the different life stages of the parasite.
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Affiliation(s)
- Miriam Bischofsberger
- Department of Tropical Medicine, Infectious Diseases and Section of Nephrology, University Medical Center Rostock, Rostock, Germany
| | - Franziska Winkelmann
- Department of Tropical Medicine, Infectious Diseases and Section of Nephrology, University Medical Center Rostock, Rostock, Germany
| | - Anne Rabes
- Department of Tropical Medicine, Infectious Diseases and Section of Nephrology, University Medical Center Rostock, Rostock, Germany
| | - Emil C Reisinger
- Department of Tropical Medicine, Infectious Diseases and Section of Nephrology, University Medical Center Rostock, Rostock, Germany
| | - Martina Sombetzki
- Department of Tropical Medicine, Infectious Diseases and Section of Nephrology, University Medical Center Rostock, Rostock, Germany.
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Murphy A, Cwiklinski K, Lalor R, O’Connell B, Robinson MW, Gerlach J, Joshi L, Kilcoyne M, Dalton JP, O’Neill SM. Fasciola hepatica Extracellular Vesicles isolated from excretory-secretory products using a gravity flow method modulate dendritic cell phenotype and activity. PLoS Negl Trop Dis 2020; 14:e0008626. [PMID: 32898175 PMCID: PMC7521716 DOI: 10.1371/journal.pntd.0008626] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 09/28/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022] Open
Abstract
Parasite-released extracellular vesicles (EVs) deliver signals to the host immune system that are critical to maintaining the long-term relationship between parasite and host. In the present study, total EVs (FhEVs) released in vitro by adults of the helminth parasite Fasciola hepatica were isolated using a recently described gravity flow method that protects their structural integrity. The FhEVs molecular cargo was defined using proteomic analysis and their surface topology characterised by glycan microarrays. The proteomic analysis identified 618 proteins, 121 of which contained putative N-linked glycosylation sites while 132 proteins contained putative O-linked glycosylation sites. Glycan arrays revealed surface-exposed glycans with a high affinity for mannose-binding lectins indicating the predominance of oligo mannose-rich glycoproteins, as well as other glycans with a high affinity for complex-type N-glycans. When added to bone-marrow derived dendritic cells isolated FhEV induced a novel phenotype that was categorised by the secretion of low levels of TNF, enhanced expression of cell surface markers (CD80, CD86, CD40, OX40L, and SIGNR1) and elevation of intracellular markers (SOCS1 and SOCS3). When FhEV-stimulated BMDCs were introduced into OT-II mice by adoptive transfer, IL-2 secretion from skin draining lymph nodes and spleen cells was inhibited in response to both specific and non-specific antigen stimulation. Immunisation of mice with a suspension of FhEV did not elicit significant immune responses; however, in the presence of alum, FhEVs induced a mixed Th1/Th2 immune response with high antigen specific antibody titres. Thus, we have demonstrated that FhEVs induce a unique phentotype in DC capable of suppressing IL-2 secretion from T-cells. Our studies add to the growing immuno-proteomic database that will be an important source for the discovery of future parasite vaccines and immunotherapeutic biologicals.
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Affiliation(s)
- Anna Murphy
- Fundamental and Translational Immunology group, School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin, Ireland
| | - Krystyna Cwiklinski
- School of Natural Sciences, Centre for One Health and Ryan Institute, National University of Ireland Galway, Galway, Ireland
| | - Richard Lalor
- Fundamental and Translational Immunology group, School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin, Ireland
| | - Barry O’Connell
- Nano Research, Dublin City University, Glasnevin, Dublin 9, Ireland
| | - Mark W. Robinson
- Institute for Global Food Security, School of Biological Sciences, Medical Biology Centre (MBC), Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Jared Gerlach
- Glycoscience Group, Advanced Glycoscience Research Cluster, School of Natural Sciences, National University of Ireland, Galway, Ireland
| | - Lokesh Joshi
- Glycoscience Group, Advanced Glycoscience Research Cluster, School of Natural Sciences, National University of Ireland, Galway, Ireland
| | - Michelle Kilcoyne
- Carbohydrate Signalling Group, Discipline of Microbiology, National University of Ireland, Galway, Ireland
| | - John P. Dalton
- School of Natural Sciences, Centre for One Health and Ryan Institute, National University of Ireland Galway, Galway, Ireland
| | - Sandra M. O’Neill
- Fundamental and Translational Immunology group, School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin, Ireland
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