Exosomes Released from Rabies Virus-Infected Cells May be Involved in the Infection Process.
TL;DR: The results showed that rabies virus infection increased the release of exosomes, and the inhibitors reduced the levels of extracellular and intracellular viral RNA, indicating that exosome may participate in the viral infection process.
About: This article is published in Virologica Sinica.The article was published on 2019-02-01 and is currently open access. It has received 15 citations till now. The article focuses on the topics: Exosome & Rabies virus.
Citations
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TL;DR: Understanding the role of EVs during viral infections is crucial to comprehend viral mechanisms and respond better to emerging viral diseases.
Abstract: Extracellular vesicles are small membrane structures containing proteins and nucleic acids that are gaining a lot of attention lately. They are produced by most cells and can be detected in several body fluids, having a huge potential in therapeutic and diagnostic approaches. EVs produced by infected cells usually have a molecular signature that is very distinct from healthy cells. For intracellular pathogens like viruses, EVs can have an even more complex function, since the viral biogenesis pathway can overlap with EV pathways in several ways, generating a continuum of particles, like naked virions, EVs containing infective viral genomes and quasi-enveloped viruses, besides the classical complete viral particles that are secreted to the extracellular space. Those particles can act in recipient cells in different ways. Besides being directly infective, they also can prime neighbor cells rendering them more susceptible to infection, block antiviral responses and deliver isolated viral molecules. On the other hand, they can trigger antiviral responses and cytokine secretion even in uninfected cells near the infection site, helping to fight the infection and protect other cells from the virus. This protective response can also backfire, when a massive inflammation facilitated by those EVs can be responsible for bad clinical outcomes. EVs can help or harm the antiviral response, and sometimes both mechanisms are observed in infections by the same virus. Since those pathways are intrinsically interlinked, understand the role of EVs during viral infections is crucial to comprehend viral mechanisms and respond better to emerging viral diseases.
41 citations
TL;DR: This review summarizes the known mechanisms of exosomes biogenesis, cargo loading, exosome release and bioengineering, which is of great importance for further exploration into the clinical applications of EVs.
Abstract: Extracellular vesicles (EVs) are nanoscale membrane vesicles released by donor cells that can be taken up by recipient cells. The study of EVs has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and disease. Exosomes, with an average diameter of ≈100 nanometers, are a subset of EVs. Different molecular families have been shown to be involved in the formation of exosomes and subsequent secretion of exosomes, which largely leads to the complexity of the form, structure and function of exosomes. In addition, because of their low immunogenicity and ability to transfer a variety of bioactive components to recipient cells, exosomes are regarded as effective drug delivery systems. This review summarizes the known mechanisms of exosomes biogenesis, cargo loading, exosomes release and bioengineering, which is of great importance for further exploration into the clinical applications of EVs.
36 citations
TL;DR: Exosomes are extracellular vesicles released by cells, both constitutively and after cell activation, and are present in different types of biological fluid, and have emerged as potential non-invasive biomarkers for the detection, prognosis and therapeutics of a myriad of diseases as mentioned in this paper.
Abstract: Exosomes are extracellular vesicles released by cells, both constitutively and after cell activation, and are present in different types of biological fluid. Exosomes are involved in the pathogenesis of diseases, such as cancer, neurodegenerative diseases, pregnancy disorders and cardiovascular diseases, and have emerged as potential non-invasive biomarkers for the detection, prognosis and therapeutics of a myriad of diseases. In this review, we describe recent advances related to the regulatory mechanisms of exosome biogenesis, release and molecular composition, as well as their role in health and disease, and their potential use as disease biomarkers and therapeutic targets. In addition, the advantages and disadvantages of their main isolation methods, characterization and cargo analysis, as well as the experimental methods used for exosome-mediated drug delivery, are discussed. Finally, we present potential perspectives for the use of exosomes in future clinical practice.
31 citations
TL;DR: This study finds that HCMV modulates EV biogenesis machinery through upregulation of the endosomal sorting complex required for transport (ESCRT) proteins, which appears to increase the activity of EVBiogenesis, since H CMV-infected fibroblasts have increased vesicle release and altered vesicles size compared to EVs from uninfected cells.
Abstract: Human cytomegalovirus (HCMV) manipulates cellular processes associated with secretory pathways within an infected cell to facilitate efficient viral replication. However, little is known about how HCMV infection alters the surrounding cellular environment to promote virus spread to uninfected cells. Extracellular vesicles (EVs) are key signaling molecules that are commonly altered in numerous disease states. Previous reports have shown that viruses commonly alter EVs, which can significantly impact infection. This study finds that HCMV modulates EV biogenesis machinery through upregulation of the endosomal sorting complex required for transport (ESCRT) proteins. This regulation appears to increase the activity of EV biogenesis, since HCMV-infected fibroblasts have increased vesicle release and altered vesicle size compared to EVs from uninfected cells. EVs generated through ESCRT-independent pathways are also beneficial to virus spread in fibroblasts, as treatment with the EV inhibitor GW4869 slowed the efficiency of HCMV spread. Importantly, the transfer of EVs purified from HCMV-infected cells enhanced virus spread. This suggests that HCMV modulates the EV pathway to transfer proviral signals to uninfected cells that prime the cellular environment for incoming infection and enhance the efficiency of virus spread.IMPORTANCE Human cytomegalovirus (HCMV) is a herpesvirus that leads to serious health consequences in neonatal or immunocompromised patients. Clinical management of infection in these at-risk groups remains a serious concern even with approved antiviral therapies available. It is necessary to increase our understanding of the cellular changes that occur during infection and their importance to virus spread. This may help to identify new targets during infection that will lead to the development of novel treatment strategies. Extracellular vesicles (EVs) represent an important method of intercellular communication in the human host. This study finds that HCMV manipulates this pathway to increase the efficiency of virus spread to uninfected cells. This finding defines a new layer of host manipulation induced by HCMV infection that leads to enhanced virus spread.
19 citations
TL;DR: The virus‐induced sepsis was discussed, which may be the cause of multiple organ failure, including myocardial injury, and if exosomes could be targeted to treat symptoms of COVID‐19.
Abstract: Coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has reached a pandemic level, spreading across the globe by affecting over 33 million people and causing over 1,009,270 deaths. SARS‐CoV‐2 is highly infectious with a high basic reproduction number (R0) of 2.2–5.7 that has led to its exponential spread. Besides, very little is known about it in terms of immunogenicity and its molecular targets. SARS‐CoV‐2 causes acute respiratory distress syndrome, followed by multiple organ failure and death in a small percentage of individuals. Cardiac injury has emerged as another dreaded outcome of COVID‐19 complications. However, a thorough understanding of the pathogenesis of SARS‐CoV‐2 is lacking. In this review, we discuss the virus, possible mechanisms of COVID‐19‐induced cardiac injury, and potential therapeutic strategies, and we explore if exosomes could be targeted to treat symptoms of COVID‐19. Furthermore, we discussed the virus‐induced sepsis, which may be the cause of multiple organ failure, including myocardial injury.
19 citations
References
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TL;DR: This unit describes different approaches for exosome purification from various sources, and discusses methods to evaluate the purity and homogeneity of the purified exosomes preparations.
Abstract: Exosomes are small membrane vesicles found in cell culture supernatants and in different biological fluids. Exosomes form in a particular population of endosomes, called multivesicular bodies (MVBs), by inward budding into the lumen of the compartment. Upon fusion of MVBs with the plasma membrane, these internal vesicles are secreted. Exosomes possess a defined set of membrane and cytosolic proteins. The physiological function of exosomes is still a matter of debate, but increasing results in various experimental systems suggest their involvement in multiple biological processes. Because both cell-culture supernatants and biological fluids contain different types of lipid membranes, it is critical to perform high-quality exosome purification. This unit describes different approaches for exosome purification from various sources, and discusses methods to evaluate the purity and homogeneity of the purified exosome preparations.
4,492 citations
"Exosomes Released from Rabies Virus..." refers methods in this paper
...Supernatants harvested from Vero cells (approximately 4 9 108) were centrifuged at 4 C and 300 9g for 10 min, 2000 9g for 20 min, and 10,000 9g for 30 min (Théry et al. 2006)....
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TL;DR: The physical properties that define exosomes as a specific population of secreted vesicles are described, their biological effects, particularly on the immune system, are summarized, and the potential roles that secretedvesicles could have as intercellular messengers are discussed.
Abstract: Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells in culture. Interest in exosomes has intensified after their recent description in antigen-presenting cells and the observation that they can stimulate immune responses in vivo. In the past few years, several groups have reported the secretion of exosomes by various cell types, and have discussed their potential biological functions. Here, we describe the physical properties that define exosomes as a specific population of secreted vesicles, we summarize their biological effects, particularly on the immune system, and we discuss the potential roles that secreted vesicles could have as intercellular messengers.
4,380 citations
"Exosomes Released from Rabies Virus..." refers background in this paper
...Exosomes are nanovesicles ranging in size from 30 to 150 nm that are released from all cells, allowing them to be detected in various body fluids (Simons and Raposo 2009; Thery et al. 2002; Yanez-Mo et al. 2015)....
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...However, exosomes have recently been described as intraluminal vesicles (ILVs), which form multivesicular bodies (MVBs) that subsequently fuse with the cytoplasmic membrane to be released into the extracellular space (Harding et al. 2013; Thery et al. 2002)....
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University of Helsinki1, Semmelweis University2, University of Szeged3, Hungarian Academy of Sciences4, University of Palermo5, Institute of Molecular Pathology and Immunology of the University of Porto6, University of Porto7, Autonomous University of Barcelona8, Instituto de Biologia Molecular e Celular9, Ikerbasque10, Harvard University11, University of Duisburg-Essen12, Salk Institute for Biological Studies13, Paracelsus Private Medical University of Salzburg14, University of Colorado Denver15, Bilkent University16, Middle East Technical University17, Statens Serum Institut18, University of Southern Denmark19, Ghent University Hospital20, Oslo University Hospital21, University of Belgrade22, University of Ljubljana23, University of Mainz24, Finnish Red Cross25, University of Gothenburg26, Latvian Biomedical Research and Study centre27, University of Applied Sciences and Arts Northwestern Switzerland FHNW28, University of Valencia29, Centro Nacional de Investigaciones Cardiovasculares30, University of Freiburg31, Utrecht University32, Trinity College, Dublin33, Catalan Institution for Research and Advanced Studies34, University of Barcelona35, International University Of Catalonia36, Aarhus University Hospital37
TL;DR: A comprehensive overview of the current understanding of the physiological roles of EVs is provided, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia.
Abstract: In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
3,690 citations
"Exosomes Released from Rabies Virus..." refers background in this paper
...Exosomes are nanovesicles ranging in size from 30 to 150 nm that are released from all cells, allowing them to be detected in various body fluids (Simons and Raposo 2009; Thery et al. 2002; Yanez-Mo et al. 2015)....
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TL;DR: Exosomes transfer not only membrane components but also nucleic acid between different cells, emphasizing their role in intercellular communication.
1,979 citations
"Exosomes Released from Rabies Virus..." refers background in this paper
...First, infected cells shed exosomes containing viral proteins and the whole virus genome, promoting the spread of infection to other cells (Nour and Modis 2014; Raab-Traub and Dittmer 2017; Simons and Raposo 2009)....
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...Exosomes are nanovesicles ranging in size from 30 to 150 nm that are released from all cells, allowing them to be detected in various body fluids (Simons and Raposo 2009; Thery et al. 2002; Yanez-Mo et al. 2015)....
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...The ILVs of MVBs may traffic to the plasma membrane, where they are released into the extracellular space by fusion with the plasma membrane (Harding et al. 2013; Simons and Raposo 2009)....
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...Exosomes are membrane-bound vesicles secreted frommost cell types and found in various biological fluids (Alenquer and Amorim 2015; Simons and Raposo 2009)....
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TL;DR: The data provide an explanation how Hsp70 reactivity in NK cells is induced by tumor-derived exosomes, and the exosome-mediated lytic activity of NK cells was blockable by HSp70-specific antibody.
Abstract: Detergent-soluble membrane vesicles are actively released by human pancreas (Colo-/Colo+) and colon (CX-/CX+) carcinoma sublines, differing in their capacity to present heat shock protein 70 (Hsp70)/Bag-4 on their plasma membranes. Floating properties, acetylcholine esterase activity, and protein composition characterized them as exosomes. An enrichment of Rab-4 documented their intracellular transport route from early endosomes to the plasma membrane. After solubilization, comparable amounts of cytosolic proteins, including tubulin, Hsp70, Hsc70, and Bag-4, but not ER-residing Grp94 and calnexin, were detectable in tumor-derived exosomes. However, with respect to the exosomal surface, only Colo+/CX+ but not Colo-/CX- derived exosomes were Hsp70 membrane positive. Therefore, concomitant with an up-regulated cell surface density of activation markers, migration and Hsp70 reactivity of natural killer (NK) cells was stimulated selectively by Hsp70/Bag-4 surface-positive exosomes, but not by their negative counterparts and tumor cell lysates. Moreover, the exosome-mediated lytic activity of NK cells was blockable by Hsp70-specific antibody. As already shown for TKD stimulation, NK cells preincubated with Hsp70 surface-positive exosomes initiated apoptosis in tumors through granzyme B release. In summary, our data provide an explanation how Hsp70 reactivity in NK cells is induced by tumor-derived exosomes.
607 citations
"Exosomes Released from Rabies Virus..." refers result in this paper
...AChE is an exosome-specific marker that has been investigated in previous studies (Cantin et al. 2008; Gastpar et al. 2005; Konadu et al. 2016; Rieu et al. 2000)....
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