1
|
Li L, Xu X, Cheng P, Yu Z, Li M, Yu Z, Cheng W, Zhang W, Sun H, Song X. Klebsiella pneumoniae derived outer membrane vesicles mediated bacterial virulence, antibiotic resistance, host immune responses and clinical applications. Virulence 2025; 16:2449722. [PMID: 39792030 PMCID: PMC11730361 DOI: 10.1080/21505594.2025.2449722] [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: 07/01/2024] [Revised: 11/14/2024] [Accepted: 12/28/2024] [Indexed: 01/12/2025] Open
Abstract
Klebsiella pneumoniae is a gram-negative pathogen that can cause multiple diseases including sepsis, urinary tract infections, and pneumonia. The escalating detections of hypervirulent and antibiotic-resistant isolates are giving rise to growing public concerns. Outer membrane vesicles (OMVs) are spherical vesicles containing bioactive substances including lipopolysaccharides, peptidoglycans, periplasmic and cytoplasmic proteins, and nucleic acids. Emerging studies have reported various roles of OMVs in bacterial virulence, antibiotic resistance, stress adaptation, and host interactions, whereas knowledge on their roles in K. pneumoniae is currently unclear. In this review, we summarized recent progress on the biogenesis, components, and biological function of K. pneumoniae OMVs, the impact and action mechanism in virulence, antibiotic resistance, and host immune response. We also deliberated on the potential of K. pneumoniae OMVs in vaccine development, as diagnostic biomarkers, and as drug nanocarriers. In conclusion, K. pneumoniae OMVs hold great promise in the prevention and control of infectious diseases, which merits further investigation.
Collapse
Affiliation(s)
- Lifeng Li
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Xinxiu Xu
- Department of Neurology, Qingdao Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Ping Cheng
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Zengyuan Yu
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Mingchao Li
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Zhidan Yu
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Weyland Cheng
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Wancun Zhang
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Huiqing Sun
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Xiaorui Song
- Henan International Joint Laboratory of Children’s Infectious Diseases, Department of Neonatology, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| |
Collapse
|
2
|
Chen J, Li Y, Quan X, Chen J, Han Y, Yang L, Zhou M, Mok GSP, Wang R, Zhao Y. Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke: a special outlook on mitochondrial delivery. Neural Regen Res 2025; 20:2181-2198. [PMID: 39101653 PMCID: PMC11759020 DOI: 10.4103/nrr.nrr-d-24-00243] [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: 02/28/2024] [Revised: 06/03/2024] [Accepted: 06/22/2024] [Indexed: 08/06/2024] Open
Abstract
Ischemic stroke is a secondary cause of mortality worldwide, imposing considerable medical and economic burdens on society. Extracellular vesicles, serving as natural nano-carriers for drug delivery, exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke. However, the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency. By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles, their delivery efficacy may be greatly improved. Furthermore, previous studies have indicated that microvesicles, a subset of large-sized extracellular vesicles, can transport mitochondria to neighboring cells, thereby aiding in the restoration of mitochondrial function post-ischemic stroke. Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components, such as proteins or deoxyribonucleic acid, or their sub-components, for extracellular vesicle-based ischemic stroke therapy. In this review, we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies. Given the complex facets of treating ischemic stroke, we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process. Moreover, given the burgeoning interest in mitochondrial delivery, we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.
Collapse
Affiliation(s)
- Jiali Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Yiyang Li
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Xingping Quan
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Jinfen Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Yan Han
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Li Yang
- Department of Pharmacy, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
| | - Manfei Zhou
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Greta Seng Peng Mok
- Department of Electrical and Computer Engineering, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Ruibing Wang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region, China
| | - Yonghua Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macao Special Administrative Region, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region, China
| |
Collapse
|
3
|
Lo KJ, Wang MH, Kuo CY, Pan MH. Optimizing Isolation Methods and Exploring the Therapeutic Potential of Lotus-Derived Extracellular Vesicles in Modulating Inflammation and Promoting Wound Healing. ACS Biomater Sci Eng 2025. [PMID: 40490711 DOI: 10.1021/acsbiomaterials.5c00377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2025]
Abstract
In the past decade, with the rise of research on plant-derived extracellular vesicles (PDEVs), scientists have been continuously exploring the bioactivity of PDEVs. Many PDEVs have been shown to possess a variety of biological activities. Given that the specific characteristics of EVs are believed to be related to their source cells, PDEVs from traditional Chinese medicinal herbs hold significant potential for development. In this study, lotus (Nelumbo nucifera Gaertn.) leaves were selected as the source of PDEVs, and the impact of different isolation methods on their characteristics was evaluated, while their potential biological activities were also assessed. Lotus-derived EVs (LDEVs) were isolated by using tangential flow filtration (TFF), ultracentrifugation (UC), density gradient ultracentrifugation (DGU), and size-exclusion chromatography (SEC), respectively. The mean sizes of LDEVs isolated by various methods were in the range of 130-160 nm. Although the LDEVs isolated by the TFF method had a lower zeta potential, it exhibited the highest purity, with a yield of 3.69 ± 0.43 × 109 particles/g lotus leaves. Notably, LDEVs isolated by different methods all demonstrated the ability to attenuate LPS-induced inflammation in RAW264.7 cells, significantly decreasing the nitrite concentration in the culture medium. Furthermore, LDEVs also showed potential for wound healing, promoting the migration of HaCaT cells in vitro. LDEVs also demonstrated internalization by RAW264.7 and HaCaT cells. These results support the potential of LDEVs for biomedical applications while also suggesting that TFF is a promising and viable strategy for large-scale PDEV isolation.
Collapse
Affiliation(s)
- Kai-Jiun Lo
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
| | - Mu-Hui Wang
- Department of Medical Research, National Taiwan University Hospital, Taipei 100225, Taiwan
| | - Ching-Yao Kuo
- BO HUI BIOTECH CO., LTD., New Taipei City 248016, Taiwan
| | - Min-Hsiung Pan
- Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| |
Collapse
|
4
|
Zhu R, Ou L, Li T, Luo C, Zou Z, Qi Q, Feng X. Effect of different fermentation substrates on rumen microorganisms and microbe-derived extracellular vesicles (EVs). Braz J Microbiol 2025; 56:1399-1409. [PMID: 40266485 PMCID: PMC12095833 DOI: 10.1007/s42770-025-01673-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 03/21/2025] [Indexed: 04/24/2025] Open
Abstract
Diet composition and microbiota play a crucial role in animal health and productivity. The study aimed to explore the effects of different fermentation substrates on rumen microbiota and their extracellular vesicles (EVs). Straw (fiber), corn starch (starch), and casein (protein) were used as substrates for in vitro fermentation. After 24 h of fermentation, samples were collected and subjected to 16 S rRNA gene sequencing to analyze rumen microbiota. Microbe-derived EVs were extracted and their morphology and particle size were determined. Results showed that fiber increased the diversity of rumen microorganisms, protein increased richness, and starch decreased both diversity and richness of the microbes. Rumen microbiota was dominated by Firmicutes in the protein group, Bacteroidota in the fiber group and Prevotella in the starch group. Principal co-ordinates analysis (PCoA) revealed significant differences in microbial community structure among the three groups. LEfSe analysis at the genus level identified that Prevotella, Succinivibrio, Clostridia_UCG_014 were enriched in the starch group, whereas Acidaminococcus, Muribaculaceae, Pyramidobacter were enriched in the protein group. For the fiber group, the enriched genera included F082 and Rikenellaceae_RC9_gut_group. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) analysis showed that the top ten microbial functions were mainly involved in signaling and cellular processes (K06142, K03310, K02030, K06147, K01990, K02004, K01992, K02014) and genetic information processing (K06180, K03088), with the fiber group showing better performance in these processes compared to other two groups. Additionally, the particle sizes of extracellular vesicles ranged from 20 to 400 nm, with an average particle distribution coefficients (PDI) close to 0.3 in each group, indicating uniform particle size. Overall, different fermentation substrates significantly affected the diversity of rumen microbes, without affecting the morphology and particle size of microbial EVs.
Collapse
Affiliation(s)
- Rongxia Zhu
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China
| | - Lijun Ou
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China
| | - Tonghao Li
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China
| | - Caiyu Luo
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China
| | - Zecheng Zou
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China
| | - Qien Qi
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China
| | - Xin Feng
- School of Animal Science and Technology, Foshan University, Foshan, 528000, China.
| |
Collapse
|
5
|
Guthrie C, Meeker AC, Self AE, Ramos-Leyva A, Clark OL, Kotey SK, Hartson SD, Liang Y, Liu L, Tan X, Cheng Y. Microvesicles Derived from Human Bronchial Epithelial Cells Regulate Macrophage Activation During Mycobacterium abscessus Infection. J Proteome Res 2025; 24:2291-2301. [PMID: 40153482 PMCID: PMC12053935 DOI: 10.1021/acs.jproteome.4c00827] [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: 09/21/2024] [Revised: 01/26/2025] [Accepted: 03/24/2025] [Indexed: 03/30/2025]
Abstract
Intercellular communication is important for host immunity in response to bacterial infections. Nontuberculous mycobacterium (NTM), such as Mycobacterium abscessus (M. ab), is a group of environmental bacteria that can cause severe lung infections in individuals with pre-existing lung conditions, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). There is limited knowledge understanding the interaction between airway epithelial cells and immune cells during NTM infections. In this study, we characterized microvesicles (MVs) released from uninfected and M. ab-infected human bronchial epithelial cells and investigated the effect of these MVs on the activation and polarization of THP-1-derived macrophages in cell culture. Our results indicate that MVs released by M. ab-infected human bronchial epithelial cells stimulated the activation of M2-polarized macrophages in cell culture when compared to MVs released by uninfected cells. Additionally, the proteomic analysis for isolated MVs showed that the proteins involved in the cell adhesion pathway were enriched in MVs from M. ab-infected human bronchial epithelial cells compared to MVs from uninfected cells. Among those, the cell surface protein, intercellular adhesion molecule 1 (ICAM-1), regulated the uptake of MVs released by M. ab-infected human bronchial epithelial cells by recipient macrophages in cell culture. In conclusion, our data suggest that in response to M. ab infection, human airway epithelial cells release MVs to modulate the activation of macrophages, which are key cells for mycobacterial intracellular survival in the host.
Collapse
Affiliation(s)
- Carlyn
M. Guthrie
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Amber C. Meeker
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Ashton E. Self
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Aidaly Ramos-Leyva
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Olivia L. Clark
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Stephen K. Kotey
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Steven D. Hartson
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Center
for Genomics and Proteomics, Oklahoma State
University, Stillwater, Oklahoma 74078, United States
| | - Yurong Liang
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
- Department
of Physiological Sciences, Oklahoma State
University, Stillwater, Oklahoma 74078, United States
| | - Lin Liu
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
- Department
of Physiological Sciences, Oklahoma State
University, Stillwater, Oklahoma 74078, United States
| | - Xuejuan Tan
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| | - Yong Cheng
- Department
of Biochemistry and Molecular Biology, Oklahoma
State University, Stillwater, Oklahoma 74078, United States
- Oklahoma
Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States
| |
Collapse
|
6
|
Rodrigues A, Weber JI, Durães-Oliveira J, Moreno C, Ferla M, de Aires Pereira M, Valério-Bolas A, de Freitas BE, Nunes T, Antunes WT, Alexandre-Pires G, Pereira da Fonseca I, Santos-Gomes GM. Extracellular Vesicles Derived from Trypanosomatids: The Key to Decoding Host-Parasite Communication. Int J Mol Sci 2025; 26:4302. [PMID: 40362539 PMCID: PMC12072767 DOI: 10.3390/ijms26094302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/21/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Trypanosomatids constitute a family of parasitic protozoa that cause significant human and veterinary diseases that are classified as neglected zoonotic diseases (NZDs). In a rapidly evolving world, these diseases have the potential to become a world health problem no longer solely associated with low-income countries. Therefore, the development of new strategies to control and restrain the dissemination of trypanosomatids is imperative. Extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed vesicles released by prokaryotic and eukaryotic cells. They can be found in diverse body fluids that carry biologically active molecules, including proteins, nucleic acids, lipids, and carbohydrates. EVs participate in cell-to-cell communication by delivering their cargo content to recipient cells. Thus, EVs play a role in regulating normal physiological processes, including immune surveillance and tissue repair, as well as being involved in pathological conditions, like cancer. In recent years, EVs have attracted significant attention from the scientific community, mainly due to their immune regulatory properties. Therefore, this review examines the role played by trypanosomatid-derived EVs in leishmaniases and trypanosomiasis, highlighting their biological role in host-parasite communication and exploring their potential future applications in controlling NZDs, especially those caused by trypanosomatids.
Collapse
Grants
- EXPL/CVT-CVT/0175/2021 (DOI 10.54499/EXPL/CVT-CVT/0175/2021) FCT-Foundation for Science and Technology, I.P.
- FPTDC/CVT-CVT/0228/2020 (DOI 10.54499/PTDC/CVT-CVT/0228/2020) FCT-Foundation for Science and Technology, I.P.
- CIISA, UIDB/00276/2020 FCT-Foundation for Science and Technology, I.P.
- Al4Animals, LA/P/0059/2020 FCT-Foundation for Science and Technology, I.P.
- CERNAS, UIDB/00681/2020 Foundation for Science and Technology, I.P.
- GHTM, UID/04413/2020 Foundation for Science and Technology, I.P.
- LA-REAL, LA/P/0117/2020) Foundation for Science and Technology, I.P.
- CEECIND/CP1725/CT0023 (10.54499/2022.00499.CEECIND/CP1725/CT0023) FCT-Foundation for Science and Technology, I.P.
- 2022.13899.BD FCT-Foundation for Science and Technology, I.P.
Collapse
Affiliation(s)
- Armanda Rodrigues
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| | - Juliana Inês Weber
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| | - João Durães-Oliveira
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| | - Cláudia Moreno
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| | - Micheli Ferla
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| | - Maria de Aires Pereira
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
- CERNAS-IPV Research Centre, Instituto Politécnico de Viseu, Campus Politécnico, Repeses, 3504-510 Viseu, Portugal
| | - Ana Valério-Bolas
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| | - Bruna Eugênia de Freitas
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
- Instituto de Ciências Biológicas, ICB, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
| | - Telmo Nunes
- Microscopy Center, Faculty of Sciences, University of Lisbon-FCUL-BioISI Ce3CE, 1749-016 Lisboa, Portugal;
| | - Wilson T. Antunes
- Instituto Universitário Militar (IUM), Centro de Investigação, Desenvolvimento e Inovação da Academia Militar (CINAMIL), Unidade Militar Laboratorial de Defesa Biológica e Química (UMLDBQ), 1849-012 Lisboa, Portugal;
| | - Graça Alexandre-Pires
- CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, 1649-004 Lisbon, Portugal; (G.A.-P.); (I.P.d.F.)
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1200-771 Lisbon, Portugal
| | - Isabel Pereira da Fonseca
- CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, 1649-004 Lisbon, Portugal; (G.A.-P.); (I.P.d.F.)
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1200-771 Lisbon, Portugal
| | - Gabriela M. Santos-Gomes
- Global Health and Tropical Medicine, GHTM, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisboa, Portugal; (J.I.W.); (J.D.-O.); (C.M.); (M.F.); (M.d.A.P.); (A.V.-B.); (B.E.d.F.); (G.M.S.-G.)
| |
Collapse
|
7
|
Abida, Alhuthali HM, Alshehri JM, Alkathiri A, Almaghrabi ROM, Alsaeed SS, Albebi SAH, Almethn RM, Alfuraydi BA, Alharbi SB, Kamal M, Imran M. Exosomes in infectious diseases: insights into leishmaniasis pathogenesis, immune modulation, and therapeutic potential. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4913-4931. [PMID: 39702600 DOI: 10.1007/s00210-024-03702-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/02/2024] [Indexed: 12/21/2024]
Abstract
Leishmaniasis continues to be a critical international health issue due to the scarcity of efficient treatment and the development of drug tolerance. New developments in the research of extracellular vesicles (EVs), especially exosomes, have revealed novel disease management approaches. Exosomes are small vesicles that transport lipids, nucleic acids, and proteins in cell signalling. Its biogenesis depends on several cellular processes, and their functions in immune response, encompassing innate and adaptive immunity, underline their function in the pathogen-host interface. Exosomes play a significant role in the pathogenesis of some parasitic infections, especially Leishmaniasis, by helping parasites escape host immunity and promote disease progression. This article explains that in the framework of parasitic diseases, exosomes can act as master regulators that define the pathogenesis of the disease, as illustrated by the engagement of exosomes in the Leishmaniasis parasite and immune escape processes. Based on many published articles on Leishmaniasis, this review aims to summarize the biogenesis of exosomes, the properties of the cargo in exosomes, and the modulation of immune responses. We delve deeper into the prospect of using exosomes for the therapy of Leishmaniasis based on the possibility of using these extracellular vesicles for drug delivery and as diagnostic and prognostic biomarkers. Lastly, we focus on the recent research perspectives and future developments, underlining the necessity to continue the investigation of exosome-mediated approaches in Leishmaniasis treatment. Thus, this review intends to draw attention to exosomes as a bright new perspective in the battle against this disabling affliction.
Collapse
Affiliation(s)
- Abida
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Jawaher Mohammad Alshehri
- Optometry Department, Faculty of Applied Medical Sciences, Albaha University, 65431, Albaha, Saudi Arabia
| | - Afnan Alkathiri
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Albaha University, 65431, Albaha, Saudi Arabia
| | - Ruba Omar M Almaghrabi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Albaha University, 65431, Albaha, Saudi Arabia
| | | | | | | | | | | | - Mehnaz Kamal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia.
- Center for Health Research, Northern Border University, Arar, Saudi Arabia.
| |
Collapse
|
8
|
Sabatke B, Rossi IV, Ramirez MI. Interaction vesicles as emerging mediators of host-pathogen molecular crosstalk and their implications for infection dynamics. FEBS Lett 2025. [PMID: 40313034 DOI: 10.1002/1873-3468.70055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/08/2025] [Accepted: 04/12/2025] [Indexed: 05/03/2025]
Abstract
Extracellular vesicles (EVs) are critical in cell communication, transfer of biomolecules, and host-pathogen interaction. A newly identified subset, "interaction vesicles" (iEVs), forms through host-pathogen contact, merging membrane elements from both. These iEVs may arise through multiple mechanisms, including direct cell-cell contact, membrane contact sites, uptake and repackaging of foreign EVs, and post-release fusion of EVs. These hybrid vesicles enable pathogens to modify host environments, aiding immune evasion and infection persistence. However, iEVs may also act in favor of the host, contributing to pathogen recognition and elimination. Advanced techniques, including proteomics and high-resolution microscopy, are beginning to clarify their composition and fusion. Yet, isolating these hybrid EVs remains challenging. Overcoming these barriers could enhance understanding of infection mechanisms and support diagnostic and therapeutic innovation.
Collapse
Affiliation(s)
- Bruna Sabatke
- Graduate Program in Microbiology, Pathology and Parasitology, Federal University of Paraná, Curitiba, Brazil
- EVAHPI - Extracellular Vesicles and Host-Parasite Interactions Research Group, Carlos Chagas Institute (Fiocruz-PR), Curitiba, Brazil
| | - Izadora Volpato Rossi
- Graduate Program in Microbiology, Pathology and Parasitology, Federal University of Paraná, Curitiba, Brazil
- EVAHPI - Extracellular Vesicles and Host-Parasite Interactions Research Group, Carlos Chagas Institute (Fiocruz-PR), Curitiba, Brazil
| | - Marcel I Ramirez
- Graduate Program in Microbiology, Pathology and Parasitology, Federal University of Paraná, Curitiba, Brazil
- EVAHPI - Extracellular Vesicles and Host-Parasite Interactions Research Group, Carlos Chagas Institute (Fiocruz-PR), Curitiba, Brazil
- Graduate Program in Cell and Molecular Biology, Federal University of Paraná, Curitiba, Brazil
| |
Collapse
|
9
|
Yuan Y, Cao K, Gao P, Wang Y, An W, Dong Y. Extracellular vesicles and bioactive peptides for regenerative medicine in cosmetology. Ageing Res Rev 2025; 107:102712. [PMID: 40032214 DOI: 10.1016/j.arr.2025.102712] [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: 11/08/2024] [Revised: 01/10/2025] [Accepted: 02/25/2025] [Indexed: 03/05/2025]
Abstract
As life quality improves and the life pressure increases, people's awareness of maintaining healthy skin and hair grows. However, the use of bioactive peptides in regenerative medical aesthetics is often constrained by the high molecular weight, which impedes skin penetration. In contrast, extracellular vesicles not only possess regenerative properties but also serve as effective carriers for bioactive peptides. Given their anti-inflammatory and bactericidal properties, capacity to promote angiogenesis, optimize collagen alignment, facilitate re-epithelialization and stimulate hair growth, extracellular vesicles become an emerging and promising solution for skin regeneration treatments. The combination of peptides and extracellular vesicles enhances therapeutic efficacy and improves the bioavailability of bioactive peptides. In this review, we summarize the functions of bioactive peptides and plant- and animal-derived extracellular vesicles in regenerative medicine with cosmetology, along with examples of their combined applications. Additionally, we provide an overview of peptides and extracellular vesicles currently available on the market and in clinical practice, discussing the challenges and solutions associated with their use.
Collapse
Affiliation(s)
- Yize Yuan
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Kailu Cao
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Peifen Gao
- National Vaccine & Serum Institute, China National Biotech Group, Sinopharm Group, Beijing 101111, China
| | - Yinan Wang
- National Vaccine & Serum Institute, China National Biotech Group, Sinopharm Group, Beijing 101111, China
| | - Wenlin An
- National Vaccine & Serum Institute, China National Biotech Group, Sinopharm Group, Beijing 101111, China.
| | - Yiyang Dong
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
| |
Collapse
|
10
|
Aakel N, Mohammed R, Fathima A, Kerzabi R, Abdallah A, Ibrahim WN. Role of Exosome in Solid Cancer Progression and Its Potential Therapeutics in Cancer Treatment. Cancer Med 2025; 14:e70941. [PMID: 40344389 PMCID: PMC12063069 DOI: 10.1002/cam4.70941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 04/14/2025] [Accepted: 04/28/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Exosomes are extracellular vesicles ranging from 40 to 100 nm in diameter that mediate intercellular communication by transferring proteins, lipids, nucleic acids, and other metabolites. In the context of cancer, exosomes influence the tumor microenvironment by carrying regulatory RNAs such as miRNA, circRNA, and lncRNA. They originate from various cells, including adipocytes, fibroblasts, and hepatocellular carcinoma (HCC) cells, and can either promote or inhibit cancer progression through pathways like MAPK and PI3K-Akt. AIM This review aims to explore the role of exosomes in the progression of solid cancers, emphasizing their self-induced activation mechanisms and how they modulate tumor behavior. METHODOLOGY A comprehensive review of recent literature was conducted, focusing on studies that investigated the biological functions of exosomes in solid tumor progression, including their molecular cargo, cellular origin, and involvement in signaling pathways. RESULTS Findings from multiple studies indicate that cancer-derived exosomes contribute to tumor proliferation, metastasis, and therapy resistance by enhancing communication within the tumor microenvironment. These vesicles activate oncogenic pathways and can serve as biomarkers or therapeutic targets due to their role in disease modulation. CONCLUSION Exosomes play a pivotal role in solid cancer progression and offer significant potential in advancing our understanding of tumor biology. Their capacity to influence key signaling pathways and facilitate intercellular communication makes them promising candidates for novel diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Nada Aakel
- Department of Biomedical ScienceCollege of Health Sciences, QU Health, Qatar UniversityDohaQatar
| | - Rawdhah Mohammed
- Department of Biomedical ScienceCollege of Health Sciences, QU Health, Qatar UniversityDohaQatar
| | - Assela Fathima
- Department of Biomedical ScienceCollege of Health Sciences, QU Health, Qatar UniversityDohaQatar
| | - Rabia Kerzabi
- Department of Biomedical ScienceCollege of Health Sciences, QU Health, Qatar UniversityDohaQatar
| | - Atiyeh Abdallah
- Department of Biomedical ScienceCollege of Health Sciences, QU Health, Qatar UniversityDohaQatar
| | - Wisam Nabeel Ibrahim
- Department of Biomedical ScienceCollege of Health Sciences, QU Health, Qatar UniversityDohaQatar
| |
Collapse
|
11
|
Sanchez NC, Roig-Lopez JL, Mobley JA, Khanal S. Proteomic signatures of retinal pigment epithelium-derived exosomes in myopic and non-myopic tree shrew eyes. Front Med (Lausanne) 2025; 12:1523211. [PMID: 40330779 PMCID: PMC12052888 DOI: 10.3389/fmed.2025.1523211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 03/17/2025] [Indexed: 05/08/2025] Open
Abstract
Purpose The retinal pigment epithelium (RPE) transmits growth signals from the neural retina to the choroid in the emmetropization pathway, but the underlying molecular mechanisms remain poorly understood. Here, we compared the proteomic profiles of RPE-derived exosomes between myopic and non-myopic eyes of tree shrews, dichromatic mammals closely related to primates. Methods Four myopic (159-210 days of visual experience, DVE) and seven non-myopic eyes (156-210 DVE) of tree shrews were included. Non-cycloplegic refractive error was measured with Nidek autorefractor, and axial ocular component dimensions were recorded with LenStar. Tissue was collected, yielding RPE-lined eyecups, which were subsequently incubated in L-15 culture media for 2 h. The RPE-derived exosomes were then enriched and purified from the incubation media by double ultracentrifugation and characterized by imaging and molecular methods. Exosomal proteins were identified and quantified with mass spectrometry, examined using GO and KEGG analyses, and compared between myopic and non-myopic samples. Results Out of 506 RPE exosomal proteins identified, 48 and 41 were unique to the myopic and non-myopic samples, respectively. There were 286 differentially expressed proteins in the myopic samples, including 79 upregulated and 70 downregulated. The top three upregulated proteins were Histone H4 (Fold Change, FC = 3.04, p = 0.09), PTB 1 (FC = 2.59, p = 0.08) and Histone H3.1 (FC = 2.59, p = 0.13), while the top three downregulated proteins were RPS5 (FC = -2.41, p=0.004), ACOT7 (FC=-2.15, p = 0.04) and CRYBB2 (FC = -2.14, p = 0.05). Other differentially expressed proteins included LUM, VCL, SEPTIN11, GPX3, SPTBN1, SEPTIN7, RPL10A, KCTD12, FGG, and FMOD. Proteomic analysis revealed a low abundance of ATP6V1B2 and crystallin beta B2, and a significant depletion of the crystallin protein family (crystallin A2, A3, and B3 subunits) in the myopic samples. The enrichment analyses showed extracellular matrix, cytoskeletal dynamic, and cell-matrix adhesion as the primary components associated with the RPE exosomal proteins in myopic eyes. Conclusion Using standard molecular and imaging techniques, this study provides the first demonstration of the ex-vivo RPE exosome biogenesis from tree shrew eyes. The results showed distinct differential expressions of the RPE exosomal proteins between the myopic and non-myopic eyes, with several proteins unique to each group. Future targeted proteomic studies of identified candidate exosomal protein signatures could elucidate the molecular mechanism of RPE exosome-mediated growth signal transmission in the emmetropization pathway.
Collapse
Affiliation(s)
- Nilda C. Sanchez
- School of Optometry, Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jose Luis Roig-Lopez
- School of Optometry, Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
| | - James A. Mobley
- Heersink School of Medicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Heersink School of Medicine, O'Neal CCC Mass Spectrometry and Proteomics Shared Resource, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Safal Khanal
- School of Optometry, Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|
12
|
Wang W, Huang Y, Lin H, Cao Y. Role of opuB in Modulating Membrane Vesicle Composition and Function in Streptococcus mutans Under Neutral and Acidic Conditions. Microorganisms 2025; 13:884. [PMID: 40284720 PMCID: PMC12029584 DOI: 10.3390/microorganisms13040884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 03/31/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Streptococcus mutans (S. mutans) plays an important role in dental caries through acid production and biofilm formation. The membrane vesicles (MVs) of S. mutans are essential for microbial physiology, biofilm activity, and acid adaptation. The OpuB transporter regulates osmotic pressure in Bacillus subtilis; however, its role in S. mutans and its MVs remains unexplored. This study investigated the effects of the opuB pathway on MV biogenesis, as well as the proteomic and lipidomic profiles under neutral (pH 7.5) and acidic (pH 5.5) conditions. Nanoflow cytometry showed that the opuB-deficient strain (Smu_opuB) produced significantly more and smaller MVs than UA159 at pH 7.5, while the difference was not significant at pH 5.5. Lipidomic analysis revealed that opuB affected the lipid composition and concentration of S. mutans MVs. Proteomic analysis identified the differential enrichment of key metabolic processes associated with stress, including DNA repair. These findings highlight that opuB is an important regulator of MV biosynthesis and composition and may affect the environmental adaptability of S. mutans by regulating MVs.
Collapse
Affiliation(s)
- Wenyu Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China; (W.W.); (Y.H.)
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China
| | - Yiyi Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China; (W.W.); (Y.H.)
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China
| | - Huancai Lin
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China; (W.W.); (Y.H.)
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China
| | - Yina Cao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China; (W.W.); (Y.H.)
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China
| |
Collapse
|
13
|
Premathilaka C, Kodithuwakku S, Midekessa G, Godakumara K, Ul Ain Reshi Q, Andronowska A, Orro T, Fazeli A. Bovine fecal extracellular vesicles: A novel noninvasive tool for understanding gut physiology and pathophysiology in calves. J Dairy Sci 2025; 108:4116-4130. [PMID: 39892598 DOI: 10.3168/jds.2024-25920] [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: 10/24/2024] [Accepted: 12/31/2024] [Indexed: 02/04/2025]
Abstract
Dairy calf gut health is linked with development and future production. Fecal extracellular vesicles (fEV) have emerged as a noninvasive tool in elucidating gut physiology and pathophysiology. Because feces is a complex matrix, the enrichment of extracellular vesicles (EV) from ruminant or preruminant feces is difficult. Nevertheless, if enriched, they have great potential as a gut health diagnostic and monitoring tool in dairy calves. Therefore, this study aimed to devise a protocol to enrich and characterize fEV from preweaning calves. We developed an fEV enrichment method by combination of differential centrifugation and double size exclusion chromatography and then characterized the fEV from the healthy calves. The study also assessed sample storage conditions, and the results indicated that storing preprocessed fecal samples at -80°C effectively preserves EV without introducing additional nanoparticles. Finally, fEV from 10-d-old healthy and Cryptosporidium spp.-positive calves were enriched, and a comparative analysis of fEV characteristics between the 2 groups was performed. Characterization results on EV specific protein biomarkers, size profile, total protein content, zeta potential, and morphology clearly established the enrichment of fEV with the developed protocol. The fEV analysis for calves positive and negative for Cryptosporidium spp. revealed a significant decrease in average nanoparticle size and zeta potential values in Cryptosporidium spp.-infected calves. Furthermore, the enriched fEV carried protein and nucleic acid cargo which could be further analyzed for other biomarkers to predict the gut physiology and pathophysiology of calves. In conclusion, our study has successfully optimized a protocol to enrich high purity grade EV from calf feces and displayed potential diagnostic application as a noninvasive tool.
Collapse
Affiliation(s)
- Chanaka Premathilaka
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia
| | - Suranga Kodithuwakku
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia; Department of Animal Science, Faculty of Agriculture, University of Peradeniya, 20400 Peradeniya, Sri Lanka
| | - Getnet Midekessa
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia; Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, Tartu University, 50411 Tartu, Estonia
| | - Kasun Godakumara
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia
| | - Qurat Ul Ain Reshi
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia; Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, Tartu University, 50411 Tartu, Estonia
| | - Aneta Andronowska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland
| | - Toomas Orro
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia
| | - Alireza Fazeli
- Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, 51006 Tartu, Estonia; Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, Tartu University, 50411 Tartu, Estonia; Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, S10 2SF Sheffield, UK.
| |
Collapse
|
14
|
Jiao J, Ma Z, Li N, Duan F, Cai X, Zuo Y, Li J, Meng Q, Qiao J. Listeria monocytogenes Modulates Macrophage Inflammatory Responses to Facilitate Its Intracellular Survival by Manipulating Macrophage-Derived Exosomal ncRNAs. Microorganisms 2025; 13:410. [PMID: 40005775 PMCID: PMC11858176 DOI: 10.3390/microorganisms13020410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/05/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Exosomes are nanoscale vesicles secreted by cells that play vital regulatory roles in intercellular communication and immune responses. Listeria monocytogenes (L. Monocytogenes, LM) is a notable Gram-positive intracellular parasitic bacterium that infects humans and diverse animal species. However, the specific biological function of exosomes secreted by macrophages during L. Monocytogenes infection (hereafter EXO-LM) remains elusive. Here, we discovered that EXO-LM stimulated the secretion of inflammation-associated cytokines by macrophages, facilitating the intracellular survival of L. monocytogenes within macrophages. Transcriptomic analysis shows that EXO-LM significantly upregulates immune recognition and inflammation-related signaling pathways in macrophages. Furthermore, a ceRNA regulatory network comprising exosomal ncRNAs and macrophage RNAs was constructed through EXO-LM transcriptome sequencing. Utilizing bioinformatics and dual-luciferase reporter assays, we identified two potential binding sites between lncRNA Rpl13a-213 and miR-132-3p. Cell transfection experiments demonstrated that Rpl13a-213 overexpression augmented pro-inflammatory cytokine expression in macrophages, in contrast to the suppression by miR-132-3p overexpression. The decrease in Rpl13a-213 upon EXO-LM stimulation enhances miR-132-3p expression, dampening the inflammatory response in macrophages and aiding L. monocytogenes intracellular survival. This study unveils the immunomodulatory function of exosomal ncRNAs originating from macrophages, which provides fresh perspectives into the mechanisms underlying macrophage inflammatory response regulation by L. monocytogenes-infected cell-derived exosomes.
Collapse
Affiliation(s)
- Jian Jiao
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Zhongmei Ma
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Nengxiu Li
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Fushuang Duan
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Xuepeng Cai
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Yufei Zuo
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Jie Li
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Qingling Meng
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| | - Jun Qiao
- College of Animal Science & Technology, Shihezi University, Shihezi 832003, China; (J.J.); (Z.M.); (N.L.)
| |
Collapse
|
15
|
Wang J, Wang X, Luo H, Xie Y, Cao H, Mao L, Liu T, Yue Y, Qian H. Extracellular vesicles in Helicobacter pylori-mediated diseases: mechanisms and therapeutic potential. Cell Commun Signal 2025; 23:79. [PMID: 39934861 PMCID: PMC11816533 DOI: 10.1186/s12964-025-02074-6] [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: 09/27/2024] [Accepted: 01/29/2025] [Indexed: 02/13/2025] Open
Abstract
Extracellular vesicles (EVs) are relevant elements for cell-to-cell communication and are considered crucial in host-pathogen interactions by transferring molecules between the pathogen and the host during infections. These structures participate in various physiological and pathological processes and are considered promising candidates as disease markers, therapeutic reagents, and drug carriers. Both H. pylori and the host epithelial cells infected by H. pylori secrete EVs, which contribute to inflammation and the development of disease phenotypes. However, many aspects of the cellular and molecular biology of EV functions remain incompletely understood due to methodological challenges in studying these small structures. This review also highlights the roles of EVs derived from H. pylori-infected cells in the pathogenesis of gastric and extragastric diseases. Understanding the specific functions of these EVs during H. pylori infections, whether are advantageous to the host or the pathogen, may help the development new therapeutic approaches to prevent disease.
Collapse
Affiliation(s)
- Jianjun Wang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Xiuping Wang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Hao Luo
- Department of Clinical Laboratory, The Second People's Hospital of Kunshan, Suzhou, Jiangsu, 215300, China
| | - Yiping Xie
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Hui Cao
- Department of Food and Nutrition Safety, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, 210003, China
| | - Lingxiang Mao
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Tingting Liu
- Science and Technology Talent Department, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Yushan Yue
- Department of Rehabilitative Medicine, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhengjiang, Jiangsu, 212013, China.
| |
Collapse
|
16
|
Li Q, Liu Q, Li S, Zuo X, Zhou H, Gao Z, Xia B. Golgi-derived extracellular vesicle production induced by SARS-CoV-2 envelope protein. Apoptosis 2025; 30:197-209. [PMID: 39580578 DOI: 10.1007/s10495-024-02035-3] [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] [Accepted: 10/21/2024] [Indexed: 11/25/2024]
Abstract
Extracellular vesicles facilitate cell-to-cell communication, and some enveloped viruses utilize these vesicles as carriers to mediate viral transmission. SARS-CoV-2 envelope protein (2-E) forms a cation channel and overexpression of 2-E led to the generation of a distinct type of large extracellular vesicles (2-E-EVs). Although 2-E-EVs have been demonstrated to facilitate viral transmission in a receptor-independent way, the characteristics and biogenesis mechanism remain enigmatic. Via lipidomics and proteomic analysis, we found 2-E-EVs are distinct from endosome-derived exosomes. 2-E-EVs are notably enriched in Golgi apparatus components, aligning with the observed fragmentation in Golgi morphology. Through live cell imaging, we established a connection between 2-E-EVs formation, Golgi fragmentation, and channel activity, emphasizing the role of 2-E-EVs as ion channel-induced extracellular vesicles. Our work highlights 2-E-EVs as distinctive Golgi-derived vesicles, contributing to a deeper understanding of 2-E channel-mediated virus-host dynamics, with implications for therapeutic strategies and drug delivery.
Collapse
Affiliation(s)
- Qiguang Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
- University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China
| | - Qian Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Shuangqu Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
- University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China
| | - Xiaoli Zuo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Hu Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
| | - Zhaobing Gao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
- Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, China.
| | - Bingqing Xia
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
| |
Collapse
|
17
|
Castellani S, Basiricò L, Maggiolino A, Lecchi C, De Palo P, Bernabucci U. Effects of milk extracellular vesicles from Holstein Friesian and Brown Swiss heat-stressed dairy cows on bovine mammary epithelial cells. J Dairy Sci 2025; 108:1978-1991. [PMID: 39662803 DOI: 10.3168/jds.2024-25133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/24/2024] [Indexed: 12/13/2024]
Abstract
The increase in ambient temperature is responsible for a behavioral, physiological, and metabolic responses known as heat stress, which affects dairy cows' general well-being, health, reproduction, and productivity. Focusing on the functioning of the mammary gland, attention has been recently paid to a new method of cell-cell communication mediated by extracellular vesicles, which with their cargo can affect the target cells' phenotypic traits, behavior, and biological functions. This study investigated whether the small extracellular vesicles (sEV) isolated from milk of heat-stressed Holstein Friesian (H) and Brown Swiss (B) cows affect the cellular response of a bovine mammary epithelial cell line (BME-UV1). To this purpose, 8 mid lactation cows, 4 of each breed fed the same diet and kept in the same barn, which experienced the same hyperthermia during a natural heat wave, were chosen to collect 2 milk different samples: under thermoneutrality (TN, d1) and under heat stress (HS, d 8) conditions. The sEV were isolated from skim milk samples through differential centrifugations, characterized for size and concentration by nanoparticle tracking analysis. Integrity of the milk sEV membranes was evaluated by transmission electron microscopy and presence of EV markers through western blotting. Then BME-UV1 cells were incubated for 24 h with different pooled milk sEVs (H-TN, H-HS, B-TN, B-HS). Cell viability and apoptosis assay, reactive oxygen species production, and mRNA expression of heat shock proteins and antioxidant genes by reverse transcription and real time PCR were determined. In vivo results showed an increase in rectal temperature and respiration rate, a reduction in milk yield both for H and B dairy cows, with a lowest decrease observed in B cows compared with H cows. In vitro results of BME-UV1 cells treated with milk sEV H-HS and B-HS showed an alteration of the cell viability and metabolic activity, by reducing or increasing reactive oxygen species accumulation, and suppressing or increasing the expression of stress-associated genes thereby modulating the response of BME-UV1 according to the animals' thermal condition and the breed. These findings indicated that the small vesicles of Brown milk triggered cellular defense against heat stress, supporting the Brown Swiss breed's thermotolerance.
Collapse
Affiliation(s)
- S Castellani
- Department of Agriculture and Forest Sciences, University of Tuscia, 01100 Viterbo, Italy
| | - L Basiricò
- Department of Agriculture and Forest Sciences, University of Tuscia, 01100 Viterbo, Italy.
| | - A Maggiolino
- Department of Veterinary Medicine, University of Bari A. Moro, 70010 Valenzano, Italy
| | - C Lecchi
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy
| | - P De Palo
- Department of Veterinary Medicine, University of Bari A. Moro, 70010 Valenzano, Italy
| | - U Bernabucci
- Department of Agriculture and Forest Sciences, University of Tuscia, 01100 Viterbo, Italy
| |
Collapse
|
18
|
Vermeire CA, Tan X, Ramos-Leyva A, Wood A, Kotey SK, Hartson SD, Liang Y, Liu L, Cheng Y. Characterization of Exosomes Released from Mycobacterium abscessus-Infected Macrophages. Proteomics 2025; 25:e202400181. [PMID: 39279549 PMCID: PMC11798717 DOI: 10.1002/pmic.202400181] [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: 05/29/2024] [Revised: 08/08/2024] [Accepted: 09/02/2024] [Indexed: 09/18/2024]
Abstract
Extracellular vesicles (EVs), such as exosomes, play a critical role in cell-to-cell communication and regulating cellular processes in recipient cells. Non-tuberculous mycobacteria (NTM), such as Mycobacterium abscessus, are a group of environmental bacteria that can cause severe lung infections in populations with pre-existing lung conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). There is limited knowledge of the engagement of EVs in the host-pathogen interactions in the context of NTM infections. In this study, we found that M. abscessus infection increased the release of a subpopulation of exosomes (CD9, CD63, and/or CD81 positive) by mouse macrophages in cell culture. Proteomic analysis of these vesicles demonstrated that M. abscessus infection affects the enrichment of host proteins in exosomes released by macrophages. When compared to exosomes from uninfected macrophages, exosomes released by M. abscessus-infected macrophages significantly improved M. abscessus growth and downregulated the intracellular level of glutamine in recipient macrophages in cell culture. Increasing glutamine concentration in the medium rescued intracellular glutamine levels and M. abscessus killing in recipient macrophages that were treated with exosomes from M. abscessus-infected macrophages. Taken together, our results indicate that exosomes may serve as extracellular glutamine eliminators that interfere with glutamine-dependent M. abscessus killing in recipient macrophages.
Collapse
Affiliation(s)
- Charlie A. Vermeire
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Xuejuan Tan
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Aidaly Ramos-Leyva
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Ava Wood
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Stephen K. Kotey
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Steven D. Hartson
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Center for Genomics and Proteomics, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Yurong Liang
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Lin Liu
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Yong Cheng
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma, USA
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA
| |
Collapse
|
19
|
Li H, Lin H, Fan T, Huang L, Zhou L, Tian X, Zhao R, Zhang Y, Yang X, Wan L, Zhong H, Jiang N, Wei C, Chen W, Hou L. Exosomes derived from syncytia induced by SARS-2-S promote the proliferation and metastasis of hepatocellular carcinoma cells. Front Cell Infect Microbiol 2025; 14:1415356. [PMID: 39844837 PMCID: PMC11750861 DOI: 10.3389/fcimb.2024.1415356] [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: 04/10/2024] [Accepted: 10/29/2024] [Indexed: 01/24/2025] Open
Abstract
Introduction Coronavirus disease 2019 (COVID-19) is characterized by fever, fatigue, dry cough, dyspnea, mild pneumonia and acute lung injury (ALI), which can lead to acute respiratory distress syndrome (ARDS), and SARS-CoV-2 can accelerate tumor progression. However, the molecular mechanism for the increased mortality in cancer patients infected with COVID-19 is unclear. Methods Colony formation and wound healing assays were performed on Huh-7 cells cocultured with syncytia. Exosomes were purified from the cell supernatant and verified by nanoparticle tracking analysis (NTA), Western blot (WB) analysis and scanning electron microscopy (SEM). Differentially expressed proteins in syncytia-derived exosomes (Syn-Exos) and their functions was analyzed by Proteomic sequencing. Syn-Exo-mediated promotion of hepatocellular carcinoma cells was measured by CCK-8 and Transwell migration assays. The mechanism by which Syn-Exos promote tumor growth was analyzed by Western blotting. A patient-derived xenotransplantation (PDX) mouse model was constructed to evaluate the pathological role of the SARS-CoV-2 spike protein (SARS-2-S). The number of syncytia in the tumor tissue sections was determined by immunofluorescence analysis. Results Syncytium formation promoted the proliferation and migration of hepatocellular carcinoma cells. Proteomic sequencing revealed that proteins that regulate cell proliferation and metastasis in Syn-Exos were significantly upregulated. Syn-Exos promote the proliferation and migration of hepatocellular carcinoma cells. Animal experiments showed that a pseudotyped lentivirus bearing SARS-2-S (SARS-2-Spp) promoted tumor development in PDX mice. More syncytia were found in tumor tissue from SARS-2-Spp mice than from VSV-Gpp mice. Conclusions Syn-Exos induced by SARS-2-S can promote the proliferation and metastasis of hepatocellular carcinoma cells.
Collapse
Affiliation(s)
- Huilong Li
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Haotian Lin
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Tinghui Fan
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Linfei Huang
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Li Zhou
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Xiaoyu Tian
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Ruzhou Zhao
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Yanhong Zhang
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Xiaopan Yang
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Luming Wan
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Hui Zhong
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Nan Jiang
- Department of Pharmacy, Medical Supplies Center of People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Congwen Wei
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Wei Chen
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Lihua Hou
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| |
Collapse
|
20
|
Bhatt DK, Boerma A, Bustos SO, Otake AH, Murillo Carrasco AG, Reis PP, Chammas R, Daemen T, Andrade LNDS. Oncolytic alphavirus-induced extracellular vesicles counteract the immunosuppressive effect of melanoma-derived extracellular vesicles. Sci Rep 2025; 15:803. [PMID: 39755711 PMCID: PMC11700145 DOI: 10.1038/s41598-024-82331-9] [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: 12/11/2023] [Accepted: 12/04/2024] [Indexed: 01/06/2025] Open
Abstract
Extracellular vesicles (EVs)-mediated communication by cancer cells contributes towards the pro-tumoral reprogramming of the tumor microenvironment. Viral infection has been observed to alter the biogenesis and cargo of EVs secreted from host cells in the context of infectious biology. However, the impact of oncolytic viruses on the cargo and function of EVs released by cancer cells remains unknown. Here we show that upon oncolytic virotherapy with Semliki Forest virus-based replicon particles (rSFV), metastatic melanoma cells release EVs with a distinct biochemical profile and do not lead to suppression of immune cells. Specifically, we demonstrate that viral infection causes a differential loading of regulatory microRNAs (miRNAs) in EVs in addition to changes in their physical features. EVs derived from cancer cells potentially suppress splenocyte proliferation and induce regulatory macrophages. In contrast, EVs obtained from rSFV-infected cells did not exhibit such effects. Our results thus show that rSFV infection induces changes in the immunomodulatory properties of melanoma EVs, which may contribute to enhancing the therapeutic efficacy of virotherapy. Finally, our results show that the use of an oncolytic virus capable of a single-round of infection allows the analysis of EVs secreted from infected cells while preventing interference from extracellular virus particles.
Collapse
Affiliation(s)
- Darshak K Bhatt
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, 9713 AV, The Netherlands
- Center for Translational Research in Oncology (LIM/24), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, CEP 01246-000, Brazil
| | - Annemarie Boerma
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, 9713 AV, The Netherlands
| | - Silvina Odete Bustos
- Center for Translational Research in Oncology (LIM/24), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, CEP 01246-000, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de Sao Paulo, São Paulo, Brazil
| | - Andréia Hanada Otake
- Center for Translational Research in Oncology (LIM/24), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, CEP 01246-000, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de Sao Paulo, São Paulo, Brazil
| | - Alexis Germán Murillo Carrasco
- Center for Translational Research in Oncology (LIM/24), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, CEP 01246-000, Brazil
- Comprehensive Center for Precision Oncology (C2PO), Universidade de Sao Paulo, São Paulo, Brazil
| | - Patrícia Pintor Reis
- Department of Surgery and Orthopedics and Experimental Research Unity (UNIPEX), Faculdade de Medicina, Universidade Estadual Paulista (UNESP), Botucatu, 18618-687, Brazil
| | - Roger Chammas
- Center for Translational Research in Oncology (LIM/24), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, CEP 01246-000, Brazil.
- Comprehensive Center for Precision Oncology (C2PO), Universidade de Sao Paulo, São Paulo, Brazil.
| | - Toos Daemen
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, 9713 AV, The Netherlands
| | - Luciana Nogueira de Sousa Andrade
- Center for Translational Research in Oncology (LIM/24), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, CEP 01246-000, Brazil.
- Comprehensive Center for Precision Oncology (C2PO), Universidade de Sao Paulo, São Paulo, Brazil.
| |
Collapse
|
21
|
Kotey SK, Tan X, Kinser AL, Liu L, Cheng Y. Host Long Noncoding RNAs as Key Players in Mycobacteria-Host Interactions. Microorganisms 2024; 12:2656. [PMID: 39770858 PMCID: PMC11728548 DOI: 10.3390/microorganisms12122656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Mycobacterial infections, caused by various species within the Mycobacterium genus, remain one of the main challenges to global health across the world. Understanding the complex interplay between the host and mycobacterial pathogens is essential for developing effective diagnostic and therapeutic strategies. Host long noncoding RNAs (lncRNAs) have emerged as key regulators in cellular response to bacterial infections within host cells. This review provides an overview of the intricate relationship between mycobacterial infections and host lncRNAs in the context of Mycobacterium tuberculosis and non-tuberculous mycobacterium (NTM) infections. Accumulation of evidence indicates that host lncRNAs play a critical role in regulating cellular response to mycobacterial infection within host cells, such as macrophages, the primary host cells for mycobacterial intracellular survival. The expression of specific host lncRNAs has been implicated in the pathogenesis of mycobacterial infections, providing potential targets for the development of novel host-directed therapies and biomarkers for TB diagnosis. In summary, this review aims to highlight the current state of knowledge regarding the involvement of host lncRNAs in mycobacterial infections. It also emphasizes their potential application as novel diagnostic biomarkers and therapeutic targets.
Collapse
Affiliation(s)
- Stephen K. Kotey
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Xuejuan Tan
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Audrey L. Kinser
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| | - Lin Liu
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Yong Cheng
- Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA; (S.K.K.); (X.T.); (A.L.K.)
- Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA;
| |
Collapse
|
22
|
Wang X, Wang J, Mao L, Yao Y. Helicobacter pylori outer membrane vesicles and infected cell exosomes: new players in host immune modulation and pathogenesis. Front Immunol 2024; 15:1512935. [PMID: 39726601 PMCID: PMC11670821 DOI: 10.3389/fimmu.2024.1512935] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
Outer membrane vesicles (OMVs) and exosomes are essential mediators of host-pathogen interactions. Elucidating their mechanisms of action offers valuable insights into diagnosing and treating infectious diseases and cancers. However, the specific interactions of Helicobacter pylori (H. pylori) with host cells via OMVs and exosomes in modulating host immune responses have not been thoroughly investigated. This review explores how these vesicles elicit inflammatory and immunosuppressive responses in the host environment, facilitate pathogen invasion of host cells, and enable evasion of host defenses, thereby contributing to the progression of gastric diseases and extra-gastric diseases disseminated through the bloodstream. Furthermore, the review discusses the challenges and future directions for investigating OMVs and exosomes, underscoring their potential as therapeutic targets in H. pylori-associated diseases.
Collapse
Affiliation(s)
- Xiuping Wang
- Department of Clinical Laboratory, The First People’s Hospital of
Kunshan, Kunshan, Jiangsu, China
| | | | | | | |
Collapse
|
23
|
Brandt P, Singha R, Ene IV. Hidden allies: how extracellular vesicles drive biofilm formation, stress adaptation, and host-immune interactions in human fungal pathogens. mBio 2024; 15:e0304523. [PMID: 39555918 PMCID: PMC11633191 DOI: 10.1128/mbio.03045-23] [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] [Indexed: 11/19/2024] Open
Abstract
Pathogenic fungi pose a significant threat to human health, especially given the rising incidence of invasive fungal infections and the emergence of drug-resistant strains. This requires the development of vaccines and the advancement of antifungal strategies. Recent studies have focused on the roles of fungal extracellular vesicles (EVs) in intercellular communication and host-pathogen interactions. EVs are nanosized, lipid membrane-bound particles that facilitate the transfer of proteins, lipids, and nucleic acids. Here, we review the multifaceted functions of EVs produced by different human fungal pathogens, highlighting their importance in the response of fungal cells to different environmental cues and their interactions with host immune cells. We summarize the current state of research on EVs and how leveraging this knowledge can lead to innovative approaches in vaccine development and antifungal treatment.
Collapse
Affiliation(s)
- Philipp Brandt
- Institut Pasteur, Université Paris Cité, Fungal Heterogeneity Group, Paris, France
| | - Rima Singha
- Institut Pasteur, Université Paris Cité, Fungal Heterogeneity Group, Paris, France
| | - Iuliana V. Ene
- Institut Pasteur, Université Paris Cité, Fungal Heterogeneity Group, Paris, France
| |
Collapse
|
24
|
Keleş S, Alakbarli J, Akgül B, Baghirova M, Imamova N, Barati A, Shikhaliyeva I, Allahverdiyev A. Nanotechnology based drug delivery systems for malaria. Int J Pharm 2024; 666:124746. [PMID: 39321903 DOI: 10.1016/j.ijpharm.2024.124746] [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: 03/22/2024] [Revised: 09/04/2024] [Accepted: 09/21/2024] [Indexed: 09/27/2024]
Abstract
Malaria, caused by Plasmodium parasites transmitted through Anopheles mosquitoes, remains a global health burden, particularly in tropical regions. The most lethal species, Plasmodium falciparum and Plasmodium vivax, pose significant threats to human health. Despite various treatment strategies, malaria continues to claim lives, with Africa being disproportionately affected. This review explores the advancements in drug delivery systems for malaria treatment, focusing on polymeric and lipid-based nanoparticles. Traditional antimalarial drugs, while effective, face challenges such as toxicity and poor bio-distribution. To overcome these issues, nanocarrier systems have been developed, aiming to enhance drug efficacy, control release, and minimize side effects. Polymeric nanocapsules, dendrimers, micelles, liposomes, lipid nanoparticles, niosomes, and exosomes loaded with antimalarial drugs are examined, providing a comprehensive overview of recent developments in nanotechnology for malaria treatment. The current state of antimalarial treatment, including combination therapies and prophylactic drugs, is discussed, with a focus on the World Health Organization's recommendations. The importance of nanocarriers in malaria management is underscored, highlighting their role in targeted drug delivery, controlled release, and improved pharmacological properties. This review bridges the gap in the literature, consolidating the latest advancements in nanocarrier systems for malaria treatment and offering insights into potential future developments in the field.
Collapse
Affiliation(s)
- Sedanur Keleş
- Faculty of Engineering, Department of Metallurgical and Materials Engineering, Karadeniz Technical University, Trabzon, Turkey
| | - Jahid Alakbarli
- The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan; Faculty of Chemistry-Metallurgy, Bioengineering Department, Yildiz Technical University, Istanbul, Turkey
| | - Buşra Akgül
- Faculty of Chemistry-Metallurgy, Bioengineering Department, Yildiz Technical University, Istanbul, Turkey
| | - Malahat Baghirova
- The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan
| | - Nergiz Imamova
- The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan
| | - Ana Barati
- The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan
| | - Inji Shikhaliyeva
- The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan
| | - Adil Allahverdiyev
- The V. Y. Akhundov Scientific Research Medical Preventive Institute, Baku, Azerbaijan.
| |
Collapse
|
25
|
Seo H, Kim S, Beck S, Song HY. Perspectives on Microbiome Therapeutics in Infectious Diseases: A Comprehensive Approach Beyond Immunology and Microbiology. Cells 2024; 13:2003. [PMID: 39682751 PMCID: PMC11640688 DOI: 10.3390/cells13232003] [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: 11/02/2024] [Revised: 11/28/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Although global life expectancy has increased over the past 20 years due to advancements in managing infectious diseases, one-fifth of people still die from infections. In response to this ongoing threat, significant efforts are underway to develop vaccines and antimicrobial agents. However, pathogens evolve resistance mechanisms, complicating their control. The COVID-19 pandemic has underscored the limitations of focusing solely on the pathogen-killing strategies of immunology and microbiology to address complex, multisystemic infectious diseases. This highlights the urgent need for practical advancements, such as microbiome therapeutics, that address these limitations while complementing traditional approaches. Our review emphasizes key outcomes in the field, including evidence of probiotics reducing disease severity and insights into host-microbiome crosstalk that have informed novel therapeutic strategies. These findings underscore the potential of microbiome-based interventions to promote physiological function alongside existing strategies aimed at enhancing host immune responses and pathogen destruction. This narrative review explores microbiome therapeutics as next-generation treatments for infectious diseases, focusing on the application of probiotics and their role in host-microbiome interactions. While offering a novel perspective grounded in a cooperative defense system, this review also addresses the practical challenges and limitations in translating these advancements into clinical settings.
Collapse
Affiliation(s)
- Hoonhee Seo
- Human Microbiome Medical Research Center (HM·MRC), School of Medicine, Soonchunhyang University, 22, Soonchunhyang-ro, Sinchang-myeon, Asan-si 31538, Chungnam-do, Republic of Korea
| | - Sukyung Kim
- Human Microbiome Medical Research Center (HM·MRC), School of Medicine, Soonchunhyang University, 22, Soonchunhyang-ro, Sinchang-myeon, Asan-si 31538, Chungnam-do, Republic of Korea
| | - Samuel Beck
- Center for Aging Research, Department of Dermatology, Chobanian & Avedisian School of Medicine, Boston University, J-607, 609 Albany, Boston, MA 02118, USA
| | - Ho-Yeon Song
- Human Microbiome Medical Research Center (HM·MRC), School of Medicine, Soonchunhyang University, 22, Soonchunhyang-ro, Sinchang-myeon, Asan-si 31538, Chungnam-do, Republic of Korea
- Department of Microbiology and Immunology, School of Medicine, Soonchunhyang University, 31, Suncheonhyang 6-gil, Cheonan-si 31151, Chungnam-do, Republic of Korea
| |
Collapse
|
26
|
Sharifpour MF, Sikder S, Wong Y, Koifman N, Thomas T, Courtney R, Seymour J, Loukas A. Characterization of Spirulina-derived extracellular vesicles and their potential as a vaccine adjuvant. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e70025. [PMID: 39676887 PMCID: PMC11635480 DOI: 10.1002/jex2.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/07/2024] [Accepted: 11/21/2024] [Indexed: 12/17/2024]
Abstract
Spirulina is an edible cyanobacterium that increasingly gaining recognition for it untapped potential in the biomanufacturing of pharmaceuticals. Despite the rapidly accumulating information on extracellular vesicles (EVs) from most other bacteria, nothing is known about Spirulina extracellular vesicles (SPEVs). This study reports the successful isolation, characterization and visualization of SPEVs for the first time and it further investigates the potential therapeutic benefits of SPEVs using a mouse model. SPEVs were isolated using ultracentrifugation and size-exclusion-chromatography. Cryo-Transmission Electron Microscopy revealed pleomorphic outer-membrane-vesicles and outer-inner-membrane-vesicles displaying diverse shapes, sizes and corona densities. To assess short- and long-term immune responses, mice were injected intraperitoneally with SPEVs, which demonstrated a significant increase in neutrophils and M1 macrophages at the injection site, indicating a pro-inflammatory effect induced by SPEVs without clinical signs of toxicity or hypersensitivity. Furthermore, SPEVs demonstrated potent adjuvanticity by enhancing antigen-specific IgG responses in mice by over 100-fold compared to an unadjuvanted model vaccine antigen. Mass-spectrometry identified 54 proteins within SPEVs, including three protein superfamily members linked to the observed pro-inflammatory effects. Our findings highlight the potential of SPEVs as a new class of vaccine adjuvant and warrant additional studies to further characterize the nature of the immune response.
Collapse
Affiliation(s)
| | - Suchandan Sikder
- Australian Institute of Tropical Health and MedicineJames Cook UniversitySmithfieldQueenslandAustralia
| | - Yide Wong
- Australian Institute of Tropical Health and MedicineJames Cook UniversitySmithfieldQueenslandAustralia
| | - Na'ama Koifman
- Centre for Microscopy and MicroanalysisThe University of QueenslandSt LuciaQueenslandAustralia
| | - Tamara Thomas
- Australian Institute of Tropical Health and MedicineJames Cook UniversitySmithfieldQueenslandAustralia
| | - Robert Courtney
- Australian Institute of Tropical Health and MedicineJames Cook UniversitySmithfieldQueenslandAustralia
| | - Jamie Seymour
- Australian Institute of Tropical Health and MedicineJames Cook UniversitySmithfieldQueenslandAustralia
| | - Alex Loukas
- Australian Institute of Tropical Health and MedicineJames Cook UniversitySmithfieldQueenslandAustralia
| |
Collapse
|
27
|
Liu H, Ouyang Z, Li S. Advances of M1 macrophages-derived extracellular vesicles in tumor therapy. Biomed Pharmacother 2024; 181:117735. [PMID: 39644871 DOI: 10.1016/j.biopha.2024.117735] [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: 09/19/2024] [Revised: 11/28/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024] Open
Abstract
Extracellular vesicles derived from classically activated M1 macrophages (M1 EVs) have shown great potential in both tumor treatment and drug delivery. M1 EVs inherit specific biological messengers from their parent cells and possess the capability to activate immune cells residing in close or distant tumor tissues for antitumor therapy. Moreover, M1 EVs are commonly used as an attractive drug delivery system due to their tumor-targeting ability, biocompatibility, and non-toxic. They can effectively encapsulate various therapeutic cargoes through specific methods such as electroporation, co-incubation, sonication, extrusion, transfection, or click chemistry reaction. In this review, we provide a comprehensive summary of the advancements in M1 EVs for tumor therapy, discussing their application prospects and existing problems.
Collapse
Affiliation(s)
- Houli Liu
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui Province 230012, China.
| | - Zhaorong Ouyang
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui Province 230012, China
| | - Siyu Li
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui Province 230012, China
| |
Collapse
|
28
|
Zhao LX, Sun Q, Wang C, Liu JJ, Yan XR, Shao MC, Yu L, Xu WH, Xu R. Toxoplasma gondii-Derived Exosomes: A Potential Immunostimulant and Delivery System for Tumor Immunotherapy Superior to Toxoplasma gondii. Int J Nanomedicine 2024; 19:12421-12438. [PMID: 39600411 PMCID: PMC11590659 DOI: 10.2147/ijn.s483626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/23/2024] [Indexed: 11/29/2024] Open
Abstract
Immunotherapies such as immune checkpoint blockade (ICB) therapy and chimeric antigen receptor T-cell (CAR-T) therapy have ushered in a new era of tumor treatment. However, most patients do not benefit from immunotherapy due to limitations such as narrow indications, low response rates, and high rates of adverse effects. Toxoplasma gondii (T. gondii), a specialized intracellular protozoan, can modulate host immune responses by inhibiting or stimulating cytokines. The ability of T. gondii to enhance an organism's immune response was found to have a direct anti-tumor effect and enhance the sensitivity of patients with tumors to ICB therapy. However, the application of T. gondii for tumor therapy faces several challenges, such as biosafety concerns. Exosomes, a subtype of extracellular vesicle that contains active components such as proteins, nucleic acids, and lipids, have become effective therapeutic tools for various diseases, including tumors. Parasites, such as T. gondii, mediate the communication of pathogens with immune cells and modulate host cellular immune responses through exosomes. Growing evidence indicates that T. gondii-derived exosomes mediate communication between pathogens and immune cells, modulate host immune responses, and have great potential as new tools for tumor therapy. In this review, we highlight recent advances in isolation and identification techniques, profiling analysis, host immunomodulatory mechanisms, and the role of T. gondii-derived exosomes in tumor immunotherapy. Additionally, we emphasize the potential of T. gondii-derived exosomes as delivery platform to enhance anti-tumor efficacy in combination with other therapies. This review proposes that T. gondii-derived exosomes may serve as a novel tool for tumor immunotherapy owing to their ability to activate host immune function and properties such as high modifiability, stability, and low toxicity. This work will assist in promoting the application of parasite exosomes in tumor therapy.
Collapse
Affiliation(s)
- Lai-Xi Zhao
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of China
| | - Qiong Sun
- Department of Stomatology, Anhui Province Direct Subordinate Hospital, Hefei, 230601, People’s Republic of China
| | - Chong Wang
- Department of Microbiology and Parasitology, School of Basic Medical Sciences, Anhui Medical University, Anhui Province Key Laboratory of Zoonoses, The Provincial Key Laboratory of Zoonoses of High Institutions in Anhui, Hefei, Anhui Province, 230032, People’s Republic of China
| | - Jia-Jia Liu
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of China
| | - Xiao-Rong Yan
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of China
| | - Meng-Ci Shao
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of China
| | - Li Yu
- Department of Microbiology and Parasitology, School of Basic Medical Sciences, Anhui Medical University, Anhui Province Key Laboratory of Zoonoses, The Provincial Key Laboratory of Zoonoses of High Institutions in Anhui, Hefei, Anhui Province, 230032, People’s Republic of China
| | - Wen-Hua Xu
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of China
| | - Rui Xu
- College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, People’s Republic of China
| |
Collapse
|
29
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Extracellular Vesicles in Viral Liver Diseases. Viruses 2024; 16:1785. [PMID: 39599900 PMCID: PMC11598962 DOI: 10.3390/v16111785] [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: 09/30/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
| |
Collapse
|
30
|
Ansa‐Addo EA, Pathak P, McCrossan MV, Volpato Rossi I, Abdullahi M, Stratton D, Lange S, Ramirez MI, Inal JM. Monocyte-derived extracellular vesicles, stimulated by Trypanosoma cruzi, enhance cellular invasion in vitro via activated TGF-β1. J Extracell Vesicles 2024; 13:e70014. [PMID: 39611395 PMCID: PMC11605483 DOI: 10.1002/jev2.70014] [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: 05/25/2023] [Revised: 09/06/2024] [Accepted: 10/24/2024] [Indexed: 11/30/2024] Open
Abstract
During cell invasion, large Extracellular Vesicle (lEV) release from host cells was dose-dependently triggered by Trypanosoma cruzi metacyclic trypomastigotes (Mtr). This lEV release was inhibited when IP3-mediated Ca2+ exit from the ER and further Ca2+ entry from plasma membrane channels was blocked, but whilst any store-independent Ca2+ entry (SICE) could continue unabated. That lEV release was equally inhibited if all entry from external sources was blocked by chelation of external Ca2+ points to the major contributor to Mtr-triggered host cell lEV release being IP3/store-mediated Ca2+ release, SICE playing a minor role. Host cell lEVs were released through Mtr interaction with host cell lipid raft domains, integrins, and mechanosensitive ion channels, whereupon [Ca2+]cyt increased (50 to 750 nM) within 15 s. lEV release and cell entry of T. cruzi, which increased up to 30 and 60 mpi, respectively, as well as raised actin depolymerization at 60 mpi, were all reduced by TRPC inhibitor, GsMTx-4. Vesicle release and infection was also reduced with RGD peptide, methyl-β-cyclodextrin, knockdown of calpain and with the calpain inhibitor, calpeptin. Restoration of lEV levels, whether with lEVs from infected or uninfected epithelial cells, did not restore invasion, but supplementation with lEVs from infected monocytes, did. We provide evidence of THP-1 monocyte-derived lEV interaction with Mtr (lipid mixing by R18-dequenching; flow cytometry showing transfer to Mtr of R18 from R18-lEVs and of LAP(TGF-β1). Active, mature TGF-β1 (at 175 pg/×105 in THP-1 lEVs) was detected in concentrated lEV-/cell-free supernatant by western blotting, only after THP-1 lEVs had interacted with Mtr. The TGF-β1 receptor (TβRI) inhibitor, SB-431542, reduced the enhanced cellular invasion due to monocyte-lEVs.
Collapse
Affiliation(s)
- Ephraim A. Ansa‐Addo
- School of Human Sciences, Cell Communication in Disease PathologyLondon Metropolitan UniversityLondonUK
- Pelotonia Institute for Immuno‐Oncology, Department of Internal MedicineThe Ohio State University Comprehensive Cancer CenterColumbusOhioUSA
| | - Paras Pathak
- School of Human Sciences, Cell Communication in Disease PathologyLondon Metropolitan UniversityLondonUK
- Medical Research Council HarwellHarwell Science and Innovation Campus, Genotyping CoreOxfordshireUK
| | | | - Izadora Volpato Rossi
- School of Human Sciences, Cell Communication in Disease PathologyLondon Metropolitan UniversityLondonUK
- School of Life and Medical Sciences, Biosciences Research GroupUniversity of HertfordshireHatfieldUK
- Carlos Chagas InstituteFundacao Oswaldo Cruz, (FIOCRUZ‐PR)CuritibaBrazil
- Postgraduate Program in Cellular and Molecular BiologyFederal University of ParanáCuritibaBrazil
| | - Mahamed Abdullahi
- School of Human Sciences, Cell Communication in Disease PathologyLondon Metropolitan UniversityLondonUK
- National Mycobacterium Reference Service‐South (NMRS‐South) ColindaleLondonUK
| | - Dan Stratton
- School of Life, Health & Chemical SciencesThe Open UniversityMilton KeynesUK
| | - Sigrun Lange
- Tissue Architecture and Regeneration Research Group, School of Life SciencesUniversity of WestminsterLondonUK
- University College London, Institute of Women's HealthLondonUK
| | - Marcel I. Ramirez
- Carlos Chagas InstituteFundacao Oswaldo Cruz, (FIOCRUZ‐PR)CuritibaBrazil
| | - Jameel M. Inal
- School of Human Sciences, Cell Communication in Disease PathologyLondon Metropolitan UniversityLondonUK
- School of Life and Medical Sciences, Biosciences Research GroupUniversity of HertfordshireHatfieldUK
| |
Collapse
|
31
|
Ebrahimi F, Modaresi Movahedi A, Sabbaghian M, Poortahmasebi V. A State-of-the-Art Review on the Recent Advances in Exosomes in Oncogenic Virus. Health Sci Rep 2024; 7:e70196. [PMID: 39558933 PMCID: PMC11570872 DOI: 10.1002/hsr2.70196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 10/04/2024] [Accepted: 10/15/2024] [Indexed: 11/20/2024] Open
Abstract
Background and Aims Oncogenic viruses are responsible for approximately 12% of human malignancies, influencing various cancer processes through intricate interactions with host cells. Exosomes (EXOs), nanometric-sized microvesicles involved in cell communication, have emerged as critical mediators in these interactions. This review aims to explore the mechanisms by which EXOs produced by cells infected with oncogenic viruses promote cancer growth, enhance viral transmissibility, and act as immunomodulators. Methods A comprehensive review was conducted, focusing on recent studies highlighting the mechanisms by which EXOs facilitate the oncogenic potential of viruses. The analysis included the characterization of exosomal content, such as microRNAs (miRNAs) and proteins, and their effects on tumor microenvironments and immune responses. A search was performed using databases including PubMed, ScienceDirect, and Google Scholar. MeSH keywords related to EXOs, oncogenic viruses, and cancer were used to retrieve relevant review, systematic, and research articles. Results Findings indicate that EXOs from oncogenic virus-infected cells carry viral components that facilitate infection and inflammation. These EXOs alter the tumor microenvironment, contributing to the development of virus-associated cancers. Additionally, the review highlights the growing interest among researchers regarding the implications of EXOs in cancer progression and their potential role in enhancing the oncogenicity of viruses. Conclusion The findings underscore the pivotal role of EXOs in mediating the oncogenic effects of viruses, suggesting that targeting exosomal pathways may provide new therapeutic avenues for managing virus-associated cancers. Further research is needed to fully elucidate the functional mechanisms of EXOs in viral oncogenesis.
Collapse
Affiliation(s)
- Fatemeh Ebrahimi
- Department of Bacteriology and VirologyFaculty of Medical Sciences, Tabriz University of Medical SciencesTabrizIran
| | - Ali Modaresi Movahedi
- Department of Medical Parasitology and MycologyFaculty of Medical Sciences, Shahid Sadoughi University of Medical SciencesYazdIran
| | - Mohammad Sabbaghian
- Department of Bacteriology and VirologyFaculty of Medical Sciences, Tabriz University of Medical SciencesTabrizIran
| | - Vahdat Poortahmasebi
- Department of Bacteriology and VirologyFaculty of Medical Sciences, Tabriz University of Medical SciencesTabrizIran
| |
Collapse
|
32
|
Chu YD, Chen MC, Yeh CT, Lai MW. Hijacking host extracellular vesicle machinery by hepatotropic viruses: current understandings and future prospects. J Biomed Sci 2024; 31:97. [PMID: 39369194 PMCID: PMC11453063 DOI: 10.1186/s12929-024-01063-0] [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: 02/18/2024] [Accepted: 06/25/2024] [Indexed: 10/07/2024] Open
Abstract
Recent advances in studies exploring the roles of extracellular vesicles (EVs) in viral transmission and replication have illuminated hepatotropic viruses, such as hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV). While previous investigations have uncovered these viruses' ability to exploit cellular EV pathways for replication and transmission, most have focused on the impacts of exosomal pathways. With an improved understanding of EVs, four main subtypes, including exosomes, microvesicles, large oncosomes, and apoptotic bodies, have been categorized based on size and biogenic pathways. However, there remains a noticeable gap in comprehensive reviews summarizing recent findings and outlining future perspectives for EV studies related to hepatotropic viruses. This review aims to consolidate insights into EV pathways utilized by hepatotropic viruses, offering guidance for the future research direction in this field. By comprehending the diverse range of hepatotropic virus-associated EVs and their role in cellular communication during productive viral infections, this review may offer valuable insights for targeting therapeutics and devising strategies to combat virulent hepatotropic virus infections and the associated incidence of liver cancer.
Collapse
Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Mi-Chi Chen
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan
- Department of Pediatric, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan.
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital, 5F., No. 15, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 333, Taiwan.
- Department of Pediatric, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
| |
Collapse
|
33
|
Wu J, Mao K, Zhang R, Fu Y. Extracellular vesicles in the pathogenesis of neurotropic viruses. Microb Pathog 2024; 195:106901. [PMID: 39218378 DOI: 10.1016/j.micpath.2024.106901] [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: 05/10/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
Neurotropic viruses, characterized by their capacity to invade the central nervous system, present a considerable challenge to public health and are responsible for a diverse range of neurological disorders. This group includes a diverse array of viruses, such as herpes simplex virus, varicella zoster virus, poliovirus, enterovirus and Japanese encephalitis virus, among others. Some of these viruses exhibit high neuroinvasiveness and neurovirulence, while others demonstrate weaker neuroinvasive and neurovirulent properties. The clinical manifestations of infections caused by neurotropic viruses can vary significantly, ranging from mild symptoms to severe life-threatening conditions. Extracellular vesicles (EVs) have garnered considerable attention due to their pivotal role in intracellular communication, which modulates the biological activity of target cells via the transport of biomolecules in both health and disease. Investigating EVs in the context of virus infection is crucial for elucidating their potential role contribution to viral pathogenesis. This is because EVs derived from virus-infected cells frequently transfer viral components to uninfected cells. Importantly, EVs released by virus-infected cells have the capacity to traverse the blood-brain barrier (BBB), thereby impacting neuronal activity and inducing neuroinflammation. In this review, we explore the roles of EVs during neurotropic virus infections in either enhancing or inhibiting viral pathogenesis. We will delve into our current comprehension of the molecular mechanisms that underpin these roles, the potential implications for the infected host, and the prospective diagnostic applications that could arise from this understanding.
Collapse
Affiliation(s)
- Junyi Wu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, PR China
| | - Kedan Mao
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, PR China
| | - Rui Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China.
| | - Yuxuan Fu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, PR China.
| |
Collapse
|
34
|
Ye J, Li D, Jie Y, Luo H, Zhang W, Qiu C. Exosome-based nanoparticles and cancer immunotherapy. Biomed Pharmacother 2024; 179:117296. [PMID: 39167842 DOI: 10.1016/j.biopha.2024.117296] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 08/23/2024] Open
Abstract
Over the past decades, cancer immunotherapy has encountered challenges such as immunogenicity, inefficiency, and cytotoxicity. Consequently, exosome-based cancer immunotherapy has gained rapid traction as a promising alternative. Exosomes, a type of extracellular vesicles (EVs) ranging from 50 to 150 nm, are self-originating and exhibit fewer side effects compared to traditional therapies. Exosome-based immunotherapy encompasses three significant areas: cancer vaccination, co-inhibitory checkpoints, and adoptive T-cell therapy. Each of these fields leverages the inherent advantages of exosomes, demonstrating substantial potential for individualized tumor therapy and precision medicine. This review aims to elucidate the reasons behind the promise of exosome-based nanoparticles as cancer therapies by examining their characteristics and summarizing the latest research advancements in cancer immunotherapy.
Collapse
Affiliation(s)
- Jiarong Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Jiangxi Province, 330000 China.
| | - Danni Li
- Second Clinical Medical School, Nanchang University, Jiangxi Province 330000, China
| | - Yiting Jie
- Second Clinical Medical School, Nanchang University, Jiangxi Province 330000, China
| | - Hongliang Luo
- Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, China
| | - Wenjun Zhang
- Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, China
| | - Cheng Qiu
- Gastrointestinal Surgery, Pingxiang People's Hospital, Jiangxi Province 330000, China.
| |
Collapse
|
35
|
Alvarado-Ocampo J, Abrahams-Sandí E, Retana-Moreira L. Overview of extracellular vesicles in pathogens with special focus on human extracellular protozoan parasites. Mem Inst Oswaldo Cruz 2024; 119:e240073. [PMID: 39319874 PMCID: PMC11421424 DOI: 10.1590/0074-02760240073] [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: 04/01/2024] [Accepted: 07/09/2024] [Indexed: 09/26/2024] Open
Abstract
Extracellular vesicles (EVs) are lipid-bilayered membrane-delimited particles secreted by almost any cell type, involved in different functions according to the cell of origin and its state. From these, cell to cell communication, pathogen-host interactions and modulation of the immune response have been widely studied. Moreover, these vesicles could be employed for diagnostic and therapeutic purposes, including infections produced by pathogens of diverse types; regarding parasites, the secretion, characterisation, and roles of EVs have been studied in particular cases. Moreover, the heterogeneity of EVs presents challenges at every stage of studies, which motivates research in this area. In this review, we summarise some aspects related to the secretion and roles of EVs from several groups of pathogens, with special focus on the most recent research regarding EVs secreted by extracellular protozoan parasites.
Collapse
Affiliation(s)
- Johan Alvarado-Ocampo
- Universidad de Costa Rica, Facultad de Microbiología, Centro de Investigación en Enfermedades Tropicales, San José, Costa Rica
| | - Elizabeth Abrahams-Sandí
- Universidad de Costa Rica, Facultad de Microbiología, Centro de Investigación en Enfermedades Tropicales, San José, Costa Rica
- Universidad de Costa Rica, Facultad de Microbiología, Departamento de Parasitología, San José, Costa Rica
| | - Lissette Retana-Moreira
- Universidad de Costa Rica, Facultad de Microbiología, Centro de Investigación en Enfermedades Tropicales, San José, Costa Rica
- Universidad de Costa Rica, Facultad de Microbiología, Departamento de Parasitología, San José, Costa Rica
| |
Collapse
|
36
|
Ozaki K, Nagahara H, Kawamura A, Ohgita T, Higashi S, Ogura K, Tsutsuki H, Iyoda S, Yokotani A, Yamaji T, Moss J, Yahiro K. Extracellular Vesicle Inhibitors Enhance Cholix-Induced Cell Death via Regulation of the JNK-Dependent Pathway. Toxins (Basel) 2024; 16:380. [PMID: 39330838 PMCID: PMC11435833 DOI: 10.3390/toxins16090380] [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: 08/02/2024] [Revised: 08/25/2024] [Accepted: 08/27/2024] [Indexed: 09/28/2024] Open
Abstract
Vibrio cholerae is an important foodborne pathogen. Cholix cytotoxin (Cholix), produced by V. cholerae, is a novel eukaryotic elongation factor 2 (eEF2) adenosine diphosphate ribosyltransferase that causes host cell death by inhibiting protein synthesis. However, the role of Cholix in the infectious diseases caused by V. cholerae remains unclear. Some bacterial cytotoxins are carried by host extracellular vesicles (EVs) and transferred to other cells. In this study, we investigated the effects of EV inhibitors and EV-regulating proteins on Cholix-induced hepatocyte death. We observed that Cholix-induced cell death was significantly enhanced in the presence of EV inhibitors (e.g., dimethyl amiloride, and desipramine) and Rab27a-knockdown cells, but it did not involve a sphingomyelin-dependent pathway. RNA sequencing analysis revealed that desipramine, imipramine, and EV inhibitors promoted the Cholix-activated c-Jun NH2-terminal kinase (JNK) pathway. Furthermore, JNK inhibition decreased desipramine-enhanced Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage. In addition, suppression of Apaf-1 by small interfering RNA further enhanced Cholix-induced PARP cleavage by desipramine. We identified a novel function of desipramine in which the stimulated JNK pathway promoted a mitochondria-independent cell death pathway by Cholix.
Collapse
Affiliation(s)
- Kazuya Ozaki
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Hiyo Nagahara
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Asaka Kawamura
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Takashi Ohgita
- Center for Instrumental Analysis, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan;
| | - Sachika Higashi
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| | - Kohei Ogura
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8501, Japan;
| | - Hiroyasu Tsutsuki
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Sunao Iyoda
- Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
| | - Atsushi Yokotani
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
- Kyoto Biken Laboratories, Inc., Kyoto 611-0041, Japan
| | - Toshiyuki Yamaji
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
- Department of Microbiology and Immunology, Faculty of Pharmacy, Juntendo University, Chiba 279-0013, Japan
| | - Joel Moss
- Clinical Care Medicine and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20824-0105, USA;
| | - Kinnosuke Yahiro
- Laboratory of Microbiology and Infection Control, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; (K.O.); (H.N.); (A.K.); (S.H.); (A.Y.)
| |
Collapse
|
37
|
Vicentini LPP, Pereira-Chioccola VL, Fux B. Involvement of extracellular vesicles in the interaction of hosts and Toxoplasma gondii. CURRENT TOPICS IN MEMBRANES 2024; 94:133-155. [PMID: 39370205 DOI: 10.1016/bs.ctm.2024.06.003] [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
Toxoplasma gondii, the causative agent of toxoplasmosis, is widely distributed. This protozoan parasite is one of the best adapted, being able to infect innumerous species of animals and different types of cells. This chapter reviews current literature on extracellular vesicles secreted by T. gondii and by its hosts. The topics describe the life cycle and transmission (1); toxoplasmosis epidemiology (2); laboratorial diagnosis approach (3); The T. gondii interaction with extracellular vesicles and miRNAs (4); and the perspectives on T. gondii infection. Each topic emphases the host immune responses to the parasite antigens and the interaction with the extracellular vesicles and miRNAs.
Collapse
Affiliation(s)
| | - Vera Lucia Pereira-Chioccola
- Laboratório de Biologia Molecular de Parasitas e Fungos, Centro de Parasitologia e Micologia Instituto Adolfo Lutz, São Paulo, SP, Brazil.
| | - Blima Fux
- Programa em Doenças Infecciosas, Centro de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitoria, ES, Brazil; Unidade de Medicina Tropical, Departamento de Patologia, Universidade Federal do Espírito Santo, Vitoria, ES, Brazil.
| |
Collapse
|
38
|
Parveen S, Bhat CV, Sagilkumar AC, Aziz S, Arya J, Dutta A, Dutta S, Show S, Sharma K, Rakshit S, Johnson JB, Nongthomba U, Banerjee A, Subramanian K. Bacterial pore-forming toxin pneumolysin drives pathogenicity through host extracellular vesicles released during infection. iScience 2024; 27:110589. [PMID: 39211544 PMCID: PMC11357855 DOI: 10.1016/j.isci.2024.110589] [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: 02/02/2024] [Revised: 06/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Streptococcus pneumoniae is a global priority respiratory pathogen that kills over a million people annually. The pore-forming cytotoxin, pneumolysin (PLY) is a major virulence factor. Here, we found that recombinant PLY as well as wild-type pneumococcal strains, but not the isogenic PLY mutant, upregulated the shedding of extracellular vesicles (EVs) harboring membrane-bound toxin from human THP-1 monocytes. PLY-EVs induced cytotoxicity and hemolysis dose-dependently upon internalization by recipient monocyte-derived dendritic cells. Proteomics analysis revealed that PLY-EVs are selectively enriched in key inflammatory host proteins such as IFI16, NLRC4, PTX3, and MMP9. EVs shed from PLY-challenged or infected cells induced dendritic cell maturation and primed them to infection. In vivo, zebrafish administered with PLY-EVs showed pericardial edema and mortality. Adoptive transfer of bronchoalveolar-lavage-derived EVs from infected mice to healthy recipients induced lung damage and inflammation in a PLY-dependent manner. Our findings identify that host EVs released during infection mediate pneumococcal pathogenesis.
Collapse
Affiliation(s)
- Saba Parveen
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
| | - Chinmayi V Bhat
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
| | - Aswathy C Sagilkumar
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
- Regional Centre for Biotechnology, Faridabad 121001, India
| | - Shaheena Aziz
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
| | - J Arya
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
| | - Asmita Dutta
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
| | - Somit Dutta
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Sautan Show
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Kuldeep Sharma
- Bacterial Pathogenesis Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Sumit Rakshit
- Bacterial Pathogenesis Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - John Bernet Johnson
- Virology Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
| | - Upendra Nongthomba
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Anirban Banerjee
- Bacterial Pathogenesis Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Karthik Subramanian
- Host-Pathogen Laboratory, Pathogen Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
- Regional Centre for Biotechnology, Faridabad 121001, India
| |
Collapse
|
39
|
Mueller S. Existing and emerging mRNA vaccines and their environmental impact: a transdisciplinary assessment. ENVIRONMENTAL SCIENCES EUROPE 2024; 36:144. [DOI: 10.1186/s12302-024-00966-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/30/2024] [Indexed: 01/05/2025]
|
40
|
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] [Download PDF] [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.
Collapse
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
| |
Collapse
|
41
|
Zhang X, Yu C, Song L. Progress on the Regulation of the Host Immune Response by Parasite-Derived Exosomes. Pathogens 2024; 13:623. [PMID: 39204224 PMCID: PMC11357678 DOI: 10.3390/pathogens13080623] [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: 07/01/2024] [Revised: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024] Open
Abstract
Exosomes are membrane-bound structures released by cells into the external environment that carry a significant amount of important cargo, such as proteins, DNA, RNA, and lipids. They play a crucial role in intercellular communication. Parasites have complex life cycles and can release exosomes at different stages. Exosomes released by parasitic pathogens or infected cells contain parasitic nucleic acids, antigenic molecules, virulence factors, drug-resistant proteins, proteases, lipids, etc. These components can regulate host gene expression across species or modulate signaling pathways, thereby dampening or activating host immune responses, causing pathological damage, and participating in disease progression. This review focuses on the means by which parasitic exosomes modulate host immune responses, elaborates on the pathogenic mechanisms of parasites, clarifies the interactions between parasites and hosts, and provides a theoretical basis and research directions for the prevention and treatment of parasitic diseases.
Collapse
Affiliation(s)
| | - Chuanxin Yu
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Provincial Medical Key Laboratory, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China;
| | - Lijun Song
- National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Provincial Medical Key Laboratory, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, China;
| |
Collapse
|
42
|
Ayilam Ramachandran R, Lemoff A, Robertson DM. Extracellular vesicles released by host epithelial cells during Pseudomonas aeruginosa infection function as homing beacons for neutrophils. Cell Commun Signal 2024; 22:341. [PMID: 38907250 PMCID: PMC11191230 DOI: 10.1186/s12964-024-01609-7] [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: 01/23/2024] [Accepted: 04/10/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND Pseudomonas aeruginosa (PA) is an opportunistic pathogen that can cause sight threatening infections in the eye and fatal infections in the cystic fibrosis airway. Extracellular vesicles (EVs) are released by host cells during infection and by the bacteria themselves; however, there are no studies on the composition and functional role of host-derived EVs during PA infection of the eye or lung. Here we investigated the composition and capacity of EVs released by PA infected epithelial cells to modulate innate immune responses in host cells. METHODS Human telomerase immortalized corneal epithelial cells (hTCEpi) cells and human telomerase immortalized bronchial epithelial cells (HBECs) were treated with a standard invasive test strain of Pseudomonas aeruginosa, PAO1, for 6 h. Host derived EVs were isolated by qEV size exclusion chromatography. EV proteomic profiles during infection were compared using mass spectrometry and functional studies were carried out using hTCEpi cells, HBECs, differentiated neutrophil-like HL-60 cells, and primary human neutrophils isolated from peripheral blood. RESULTS EVs released from PA infected corneal epithelial cells increased pro-inflammatory cytokine production in naïve corneal epithelial cells and induced neutrophil chemotaxis independent of cytokine production. The EVs released from PA infected bronchial epithelial cells were also chemotactic although they failed to induce cytokine secretion from naïve HBECs. At the proteomic level, EVs derived from PA infected corneal epithelial cells exhibited lower complexity compared to bronchial epithelial cells, with the latter having reduced protein expression compared to the non-infected control. CONCLUSIONS This is the first study to comprehensively profile EVs released by corneal and bronchial epithelial cells during Pseudomonas infection. Together, these findings show that EVs released by PA infected corneal and bronchial epithelial cells function as potent mediators of neutrophil migration, contributing to the exuberant neutrophil response that occurs during infection in these tissues.
Collapse
Affiliation(s)
| | - Andrew Lemoff
- The Departments of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA
| | - Danielle M Robertson
- The Departments of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
- The Department of Ophthalmology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, 75390-9057, Dallas, TX, USA.
| |
Collapse
|
43
|
Giannessi F, Percario Z, Lombardi V, Sabatini A, Sacchi A, Lisi V, Battistini L, Borsellino G, Affabris E, Angelini DF. Macrophages treated with interferons induce different responses in lymphocytes via extracellular vesicles. iScience 2024; 27:109960. [PMID: 38832015 PMCID: PMC11144789 DOI: 10.1016/j.isci.2024.109960] [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: 11/30/2023] [Revised: 04/09/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024] Open
Abstract
Limited information exists regarding the impact of interferons (IFNs) on the information carried by extracellular vesicles (EVs). This study aimed at investigating whether IFN-α2b, IFN-β, IFN-γ, and IFN-λ1/2 modulate the content of EVs released by primary monocyte-derived macrophages (MDM). Small-EVs (sEVs) were purified by size exclusion chromatography from supernatants of MDM treated with IFNs. To characterize the concentration and dimensions of vesicles, nanoparticle tracking analysis was used. SEVs surface markers were examined by flow cytometry. IFN treatments induced a significant down-regulation of the exosomal markers CD9, CD63, and CD81 on sEVs, and a significant modulation of some adhesion molecules, major histocompatibility complexes and pro-coagulant proteins, suggesting IFNs influence biogenesis and shape the immunological asset of sEVs. SEVs released by IFN-stimulated MDM also impact lymphocyte function, showing significant modulation of lymphocyte activation and IL-17 release. Altogether, our results show that sEVs composition and activity are affected by IFN treatment of MDM.
Collapse
Affiliation(s)
- Flavia Giannessi
- Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via Ardeatina 306-354, 00179 Rome, Italy
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Zulema Percario
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Valentina Lombardi
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Andrea Sabatini
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Alessandra Sacchi
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Veronica Lisi
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Luca Battistini
- Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via Ardeatina 306-354, 00179 Rome, Italy
| | - Giovanna Borsellino
- Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via Ardeatina 306-354, 00179 Rome, Italy
| | - Elisabetta Affabris
- Laboratory of Molecular Virology and Antimicrobial Immunity, Department of Science, Roma Tre University, 00146 Rome, Italy
| | - Daniela F. Angelini
- Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via Ardeatina 306-354, 00179 Rome, Italy
| |
Collapse
|
44
|
Kanannejad Z, Arab S, Soleimanian S, Mazare A, Kheshtchin N. Exosomes in asthma: Underappreciated contributors to the pathogenesis and novel therapeutic tools. Immun Inflamm Dis 2024; 12:e1325. [PMID: 38934401 PMCID: PMC11209551 DOI: 10.1002/iid3.1325] [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: 02/12/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
OBJECTIVE Asthma, a chronic inflammatory disease with diverse pathomechanisms, presents challenges in developing personalized diagnostic and therapeutic approaches. This review aims to provide a comprehensive overview of the role of exosomes, small extracellular vesicles, in asthma pathophysiology and explores their potential as diagnostic biomarkers and therapeutic tools. METHODS A literature search was conducted to identify recent studies investigating the involvement of exosomes in asthma. The retrieved articles were analyzed to extract relevant information on the role of exosomes in maintaining lung microenvironment homeostasis, regulating inflammatory responses, and their diagnostic and therapeutic potential for asthma. RESULTS Exosomes secreted by various cell types, have emerged as crucial mediators of intercellular communication in healthy and diseased conditions. Evidence suggest that exosomes play a significant role in maintaining lung microenvironment homeostasis and contribute to asthma pathogenesis by regulating inflammatory responses. Differential exosomal content between healthy individuals and asthmatics holds promise for the development of novel asthma biomarkers. Furthermore, exosomes secreted by immune and nonimmune cells, as well as those detected in biofluids, demonstrate potential in promoting or regulating immune responses, making them attractive candidates for designing new treatment strategies for inflammatory conditions such as asthma. CONCLUSION Exosomes, with their ability to modulate immune responses and deliver therapeutic cargo, offer potential as targeted therapeutic tools in asthma management. Further research and clinical trials are required to fully understand the mechanisms underlying exosome-mediated effects and translate these findings into effective diagnostic and therapeutic strategies for asthma patients.
Collapse
Affiliation(s)
- Zahra Kanannejad
- Allergy Research CenterShiraz University of Medical SciencesShirazIran
| | - Samaneh Arab
- Department of Tissue Engineering and Applied Cell Sciences, School of MedicineSemnan University of Medical SciencesSemnanIran
| | | | - Amirhossein Mazare
- Department of Immunology, School of MedicineShiraz University of Medical SciencesShirazIran
| | - Nasim Kheshtchin
- Allergy Research CenterShiraz University of Medical SciencesShirazIran
- Department of Immunology, School of MedicineShiraz University of Medical SciencesShirazIran
| |
Collapse
|
45
|
Mohammadi A, Shabani R, Bashiri Z, Rafiei S, Asgari H, Koruji M. Therapeutic potential of exosomes in spermatogenesis regulation and male infertility. Biol Cell 2024; 116:e2300127. [PMID: 38593304 DOI: 10.1111/boc.202300127] [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: 01/21/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Spermatogenesis is a fundamental process crucial for male reproductive health and fertility. Exosomes, small membranous vesicles released by various cell types, have recently garnered attention for their role in intercellular communication. OBJECTIVE This review aims to comprehensively explore the role of exosomes in regulating spermatogenesis, focusing on their involvement in testicular development and cell-to-cell communication. METHODS A systematic examination of literature was conducted to gather relevant studies elucidating the biogenesis, composition, and functions of exosomes in the context of spermatogenesis. RESULTS Exosomes play a pivotal role in orchestrating the complex signaling networks required for proper spermatogenesis. They facilitate the transfer of key regulatory molecules between different cell populations within the testes, including Sertoli cells, Leydig cells, and germ cells. CONCLUSION The emerging understanding of exosome-mediated communication sheds light on novel mechanisms underlying spermatogenesis regulation. Further research in this area holds promise for insights into male reproductive health and potential therapeutic interventions.
Collapse
Affiliation(s)
- Amirhossein Mohammadi
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ronak Shabani
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Reproductive Sciences and Technology Research Center, Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Bashiri
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Omid Fertility & Infertility Clinic, Hamedan, Iran
| | - Sara Rafiei
- Department of Botany and Plant Sciences, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Hamidreza Asgari
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Morteza Koruji
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
46
|
Yavuz B, Mutlu EC, Ahmed Z, Ben-Nissan B, Stamboulis A. Applications of Stem Cell-Derived Extracellular Vesicles in Nerve Regeneration. Int J Mol Sci 2024; 25:5863. [PMID: 38892052 PMCID: PMC11172915 DOI: 10.3390/ijms25115863] [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: 03/06/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Extracellular vesicles (EVs), including exosomes, microvesicles, and other lipid vesicles derived from cells, play a pivotal role in intercellular communication by transferring information between cells. EVs secreted by progenitor and stem cells have been associated with the therapeutic effects observed in cell-based therapies, and they also contribute to tissue regeneration following injury, such as in orthopaedic surgery cases. This review explores the involvement of EVs in nerve regeneration, their potential as drug carriers, and their significance in stem cell research and cell-free therapies. It underscores the importance of bioengineers comprehending and manipulating EV activity to optimize the efficacy of tissue engineering and regenerative therapies.
Collapse
Affiliation(s)
- Burcak Yavuz
- Vocational School of Health Services, Altinbas University, 34147 Istanbul, Turkey;
| | - Esra Cansever Mutlu
- Biomaterials Research Group, School of Metallurgy and Materials, College of Engineering and Physical Science, University of Birmingham, Birmingham B15 2TT, UK;
| | - Zubair Ahmed
- Neuroscience & Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston B15 2TT, UK
| | - Besim Ben-Nissan
- Translational Biomaterials and Medicine Group, School of Life Sciences, University of Technology Sydney, P.O. Box 123, Broadway, NSW 2007, Australia;
| | - Artemis Stamboulis
- Biomaterials Research Group, School of Metallurgy and Materials, College of Engineering and Physical Science, University of Birmingham, Birmingham B15 2TT, UK;
| |
Collapse
|
47
|
Khabir M, Blanchet M, Angelo L, Loucif H, van Grevenynghe J, Bukong TN, Labonté P. Exosomes as Conduits: Facilitating Hepatitis B Virus-Independent Hepatitis D Virus Transmission and Propagation in Hepatocytes. Viruses 2024; 16:825. [PMID: 38932118 PMCID: PMC11209184 DOI: 10.3390/v16060825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/02/2024] [Accepted: 05/16/2024] [Indexed: 06/28/2024] Open
Abstract
A number of research studies, including ours, have spotlighted exosomes as critical facilitators of viral dissemination. While hepatitis B virus (HBV) transmission through exosomes has been studied, the focus on its satellite virus, the hepatitis delta virus (HDV), has been unexplored in this context. HDV, although being a defective virus, can replicate its genome autonomously within hepatocytes, independently of HBV. Investigations on Huh7 cells revealed an intriguing phenomenon: the HDV proteins, S-HDAg and L-HDAg, are transmitted between cells without a complete viral structure. Detailed analysis further revealed that the expression of these proteins not only bolstered exosome secretion but also ensured their enrichment within these vesicles. Our experimental approach utilized transfection of various plasmids to examine the role of HDV RNA and proteins in the process. One salient finding was the differential propagation of the HDV proteins S-HDAg and L-HDAg, suggesting intricate molecular mechanisms behind their transmission. Notably, the purity of our exosome preparations was monitored using markers such as TSG101 and CD81. Importantly, these exosomes were found to carry both HDV RNA and proteins, highlighting their role in HDV dissemination. This novel study underscores the role of exosomes in mediating the transmission of HDV components between hepatocytes independent of HBV. These revelations about the exosomal pathway of HDV transmission provide a foundation for the development of innovative therapeutic strategies against HDV infections.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Patrick Labonté
- INRS–Centre Armand-Frappier Santé Biotechnologie, Laval, QC H7V 1B7, Canada; (M.K.); (M.B.); (L.A.); (H.L.); (J.v.G.); (T.N.B.)
| |
Collapse
|
48
|
Javdani-Mallak A, Salahshoori I. Environmental pollutants and exosomes: A new paradigm in environmental health and disease. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 925:171774. [PMID: 38508246 DOI: 10.1016/j.scitotenv.2024.171774] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/16/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024]
Abstract
This study investigates the intricate interplay between environmental pollutants and exosomes, shedding light on a novel paradigm in environmental health and disease. Cellular stress, induced by environmental toxicants or disease, significantly impacts the production and composition of exosomes, crucial mediators of intercellular communication. The heat shock response (HSR) and unfolded protein response (UPR) pathways, activated during cellular stress, profoundly influence exosome generation, cargo sorting, and function, shaping intercellular communication and stress responses. Environmental pollutants, particularly lipophilic ones, directly interact with exosome lipid bilayers, potentially affecting membrane stability, release, and cellular uptake. The study reveals that exposure to environmental contaminants induces significant changes in exosomal proteins, miRNAs, and lipids, impacting cellular function and health. Understanding the impact of environmental pollutants on exosomal cargo holds promise for biomarkers of exposure, enabling non-invasive sample collection and real-time insights into ongoing cellular responses. This research explores the potential of exosomal biomarkers for early detection of health effects, assessing treatment efficacy, and population-wide screening. Overcoming challenges requires advanced isolation techniques, standardized protocols, and machine learning for data analysis. Integration with omics technologies enhances comprehensive molecular analysis, offering a holistic understanding of the complex regulatory network influenced by environmental pollutants. The study underscores the capability of exosomes in circulation as promising biomarkers for assessing environmental exposure and systemic health effects, contributing to advancements in environmental health research and disease prevention.
Collapse
Affiliation(s)
- Afsaneh Javdani-Mallak
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Iman Salahshoori
- Department of Polymer Processing, Iran Polymer and Petrochemical Institute, Tehran, Iran; Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| |
Collapse
|
49
|
Guo H, Fei L, Yu H, Li Y, Feng Y, Wu S, Wang Y. Exosome-encapsulated lncRNA HOTAIRM1 contributes to PM 2.5-aggravated COPD airway remodeling by enhancing myofibroblast differentiation. SCIENCE CHINA. LIFE SCIENCES 2024; 67:970-985. [PMID: 38332218 DOI: 10.1007/s11427-022-2392-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 02/20/2023] [Indexed: 02/10/2024]
Abstract
Emphysema, myofibroblast accumulation and airway remodeling can occur in the lungs due to exposure to atmospheric pollution, especially fine particulate matter (PM2.5), leading to chronic obstructive pulmonary disease (COPD). Specifically, bronchial epithelium-fibroblast communication participates in airway remodeling, which results in COPD. An increasing number of studies are now being conducted on the role of exosome-mediated cell-cell communication in disease pathogenesis. Here, we investigated whether exosomes generated from bronchial epithelial cells could deliver information to normal stromal fibroblasts and provoke cellular responses, resulting in airway obstruction in COPD. We studied the mechanism of exosome-mediated intercellular communication between human bronchial epithelial (HBE) cells and primary lung fibroblasts (pLFs). We found that PM2.5-induced HBE-derived exosomes promoted myofibroblast differentiation in pLFs. Then, the exosomal lncRNA expression profiles derived from PM2.5-treated HBE cells and nontreated HBE cells were investigated using an Agilent Human LncRNA Array. Combining coculture assays and direct exosome treatment, we found that HBE cell-derived exosomal HOTAIRM1 facilitated the myofibroblast differentiation of pLFs. Surprisingly, we discovered that exosomal HOTAIRM1 enhanced pLF proliferation to secrete excessive collagen secretion, leading to airway obstruction by stimulating the TGF-β/SMAD3 signaling pathway. Significantly, PM2.5 reduced FEV1/FVC and FEV1 and increased the level of serum exosomal HOTAIRM1 in healthy people; moreover, serum exosomal HOTAIRM1 was associated with PM2.5-related reductions in FEV1/FVC and FVC. These findings show that PM2.5 triggers alterations in exosome components and clarify that one of the paracrine mediators of myofibroblast differentiation is bronchial epithelial cell-derived HOTAIRM1, which has the potential to be an effective prevention and therapeutic target for PM2.5-induced COPD.
Collapse
Affiliation(s)
- Huaqi Guo
- The Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Luo Fei
- The Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Hengyi Yu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China
| | - Yan Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China
| | - Yan Feng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China
| | - Shaowei Wu
- Department of Occupational and Environmental Health Sciences, School of Public Health, Xi'an Jiao Tong University Health Science Center, Xi'an, 710049, China.
| | - Yan Wang
- The Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China.
| |
Collapse
|
50
|
Xu X, Gao S, Zuo Q, Gong J, Song X, Liu Y, Xiao J, Zhai X, Sun H, Zhang M, Gao X, Guo D. Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery. Pharmaceutics 2024; 16:601. [PMID: 38794264 PMCID: PMC11125651 DOI: 10.3390/pharmaceutics16050601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/18/2024] [Accepted: 04/25/2024] [Indexed: 05/26/2024] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of -31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.
Collapse
Affiliation(s)
- Xiaolin Xu
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Shasha Gao
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Qindan Zuo
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Jiahao Gong
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Xinhao Song
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Yongshi Liu
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Jing Xiao
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Xiaofeng Zhai
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
- Academy for Advanced Interdisciplinary Studies, Nanjing Agricultural University, Nanjing 210095, China
| | - Haifeng Sun
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Mingzhi Zhang
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Xiuge Gao
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| | - Dawei Guo
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
| |
Collapse
|