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Article ; Online: Emerging role of extracellular vesicles in multiple sclerosis: From cellular surrogates to pathogenic mediators and beyond.

Palacio, Paola Loreto / Pleet, Michelle L / Reátegui, Eduardo / Magaña, Setty M

2023 Volume 377, Page(s) 578064

Abstract: Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS) driven by a complex interplay of genetic and environmental factors. While the therapeutic arsenal has expanded significantly for management of ... ...

Abstract	Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS) driven by a complex interplay of genetic and environmental factors. While the therapeutic arsenal has expanded significantly for management of relapsing forms of MS, treatment of individuals with progressive MS is suboptimal. This treatment inequality is in part due to an incomplete understanding of pathomechanisms at different stages of the disease-underscoring the critical need for new biomarkers. Extracellular vesicles (EVs) and their bioactive cargo have emerged as endogenous nanoparticles with great theranostic potential-as diagnostic and prognostic biomarkers and ultimately as therapeutic candidates for precision nanotherapeutics. The goals of this review are to: 1) summarize the current data investigating the role of EVs and their bioactive cargo in MS pathogenesis, 2) provide a high level overview of advances and challenges in EV isolation and characterization for translational studies, and 3) conclude with future perspectives on this evolving field.
MeSH term(s)	Humans ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis/therapy ; Extracellular Vesicles ; Central Nervous System ; Biomarkers ; Cell Communication
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-03-11
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2023.578064
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Article ; Online: Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation.

DeMarino, Catherine / Cowen, Maria / Williams, Anastasia / Khatkar, Pooja / Abulwerdi, Fardokht A / Henderson, Lisa / Denniss, Julia / Pleet, Michelle L / Luttrell, Delores R / Vaisman, Iosif / Liotta, Lance A / Steiner, Joseph / Le Grice, Stuart F J / Nath, Avindra / Kashanchi, Fatah

Viruses

2024 Volume 16, Issue 4

Abstract: Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has ... ...

Abstract	Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.
MeSH term(s)	Extracellular Vesicles/metabolism ; Humans ; Toll-Like Receptor 3/metabolism ; Toll-Like Receptor 3/genetics ; HIV-1/physiology ; HIV Infections/virology ; HIV Infections/metabolism ; HIV Infections/drug therapy ; Autophagy/drug effects ; RNA, Viral/metabolism ; RNA, Viral/genetics
Chemical Substances	Toll-Like Receptor 3 ; TLR3 protein, human ; RNA, Viral
Language	English
Publishing date	2024-04-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v16040643
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Article ; Online: Extracellular Vesicle Refractive Index Derivation Utilizing Orthogonal Characterization.

Pleet, Michelle L / Cook, Sean / Tang, Vera A / Stack, Emily / Ford, Verity J / Lannigan, Joanne / Do, Ngoc / Wenger, Ellie / Fraikin, Jean-Luc / Jacobson, Steven / Jones, Jennifer C / Welsh, Joshua A

Nano letters

2023 Volume 23, Issue 20, Page(s) 9195–9202

Abstract: The analysis of small particles, including extracellular vesicles and viruses, is contingent on their ability to scatter sufficient light to be detected. These detection methods include flow cytometry, nanoparticle tracking analysis, and single particle ... ...

Abstract	The analysis of small particles, including extracellular vesicles and viruses, is contingent on their ability to scatter sufficient light to be detected. These detection methods include flow cytometry, nanoparticle tracking analysis, and single particle reflective image sensing. To standardize measurements and enable orthogonal comparisons between platforms, a quantifiable limit of detection is required. The main parameters that dictate the amount of light scattered by particles include size, morphology, and refractive index. To date, there has been a lack of accessible techniques for measuring the refractive index of nanoparticles at a single-particle level. Here, we demonstrate two methods of deriving a small particle refractive index using orthogonal measurements with commercially available platforms. These methods can be applied at either a single-particle or population level, enabling the integration of diameter and scattering cross section values to derive the refractive index using Mie theory.
MeSH term(s)	Humans ; Refractometry ; Extracellular Vesicles ; Flow Cytometry/methods ; Nanoparticles
Language	English
Publishing date	2023-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	1530-6992
ISSN (online)	1530-6992
DOI	10.1021/acs.nanolett.3c00562
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Article ; Online: Viral Immune signatures from cerebrospinal fluid extracellular vesicles and particles in HAM and other chronic neurological diseases.

Pleet, Michelle L / Welsh, Joshua A / Stack, Emily H / Cook, Sean / Johnson, Dove-Anna / Killingsworth, Bryce / Traynor, Tim / Clauze, Annaliese / Hughes, Randall / Monaco, Maria Chiara / Ngouth, Nyater / Ohayon, Joan / Enose-Akahata, Yoshimi / Nath, Avindra / Cortese, Irene / Reich, Daniel S / Jones, Jennifer C / Jacobson, Steven

Frontiers in immunology

2023 Volume 14, Page(s) 1235791

Abstract: Background and objectives: Extracellular vesicles and particles (EVPs) are released from virtually all cell types, and may package many inflammatory factors and, in the case of infection, viral components. As such, EVPs can play not only a direct role ... ...

Abstract	Background and objectives: Extracellular vesicles and particles (EVPs) are released from virtually all cell types, and may package many inflammatory factors and, in the case of infection, viral components. As such, EVPs can play not only a direct role in the development and progression of disease but can also be used as biomarkers. Here, we characterized immune signatures of EVPs from the cerebrospinal fluid (CSF) of individuals with HTLV-1-associated myelopathy (HAM), other chronic neurologic diseases, and healthy volunteers (HVs) to determine potential indicators of viral involvement and mechanisms of disease. Methods: We analyzed the EVPs from the CSF of HVs, individuals with HAM, HTLV-1-infected asymptomatic carriers (ACs), and from patients with a variety of chronic neurologic diseases of both known viral and non-viral etiologies to investigate the surface repertoires of CSF EVPs during disease. Results: Significant increases in CD8+ and CD2+ EVPs were found in HAM patient CSF samples compared to other clinical groups ( Discussion: These data suggest that CD8+ and CD2+ CSF EVPs may be important as: 1) potential biomarkers and indicators of disease pathways for viral-mediated neurological diseases, particularly HAM, and 2) as possible meditators of the disease process in infected individuals.
MeSH term(s)	Humans ; Paraparesis, Tropical Spastic ; Central Nervous System ; Extracellular Vesicles ; Nervous System Diseases ; CD40 Antigens ; Chronic Disease
Chemical Substances	CD40 Antigens
Language	English
Publishing date	2023-08-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1235791
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Article ; Online: Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals.

Sampey, Gavin C / Iordanskiy, Sergey / Pleet, Michelle L / DeMarino, Catherine / Romerio, Fabio / Mahieux, Renaud / Kashanchi, Fatah

Viruses

2020 Volume 12, Issue 10

Abstract: Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. ... ...

Abstract	Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.
MeSH term(s)	Anti-HIV Agents/pharmacology ; Databases, Pharmaceutical ; Drug Discovery ; Drug Repositioning ; HIV Infections/drug therapy ; HIV-1/drug effects ; HeLa Cells ; Humans ; Jurkat Cells ; Proviruses/drug effects ; Transcriptional Activation/drug effects
Chemical Substances	Anti-HIV Agents
Keywords	covid19
Language	English
Publishing date	2020-09-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12101067
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Article ; Online: Isolation of Exosomes from HTLV-Infected Cells.

Barclay, Robert A / Pleet, Michelle L / Akpamagbo, Yao / Noor, Kinza / Mathiesen, Allison / Kashanchi, Fatah

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1582, Page(s) 57–75

Abstract: Exosomes are small vesicles, approximately 30-100 nm in diameter, that transport various cargos, such as proteins and nucleic acids, between cells. It has been previously shown that exosomes can also transport viral proteins, such as the HTLV protein Tax, ...

Abstract	Exosomes are small vesicles, approximately 30-100 nm in diameter, that transport various cargos, such as proteins and nucleic acids, between cells. It has been previously shown that exosomes can also transport viral proteins, such as the HTLV protein Tax, and viral RNAs, potentially contributing to disease pathogenesis. Therefore, it is important to understand their impact on recipient cells. Here, we describe methods of isolating and purifying exosomes from cell culture or tissue through ultracentrifugation, characterizing exosomes by surface biomarkers, and assays that evaluate the effect of exosomes on cells.
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-6872-5_5
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Article ; Online: The Role of Exosomal VP40 in Ebola Virus Disease.

Pleet, Michelle L / DeMarino, Catherine / Lepene, Benjamin / Aman, M Javad / Kashanchi, Fatah

DNA and cell biology

2017 Volume 36, Issue 4, Page(s) 243–248

Abstract: Ebola virus (EBOV) can cause a devastating hemorrhagic disease, leading to death in a short period of time. After infection, the resulting EBOV disease results in high levels of circulating cytokines, endothelial dysfunction, coagulopathy, and bystander ... ...

Abstract	Ebola virus (EBOV) can cause a devastating hemorrhagic disease, leading to death in a short period of time. After infection, the resulting EBOV disease results in high levels of circulating cytokines, endothelial dysfunction, coagulopathy, and bystander lymphocyte apoptosis in humans and nonhuman primates. The VP40 matrix protein of EBOV is essential for viral assembly and budding from the host cell. Recent data have shown that VP40 exists in the extracellular environment, including in exosomes, and exosomal VP40 can impact the viability of recipient immune cells, including myeloid and T cells, through the regulation of the RNAi and endosomal sorting complexes required for transport pathways. In this study, we discuss the latest findings of the impact of exosomal VP40 on immune cells in vitro and its potential implications for pathogenesis in vivo.
MeSH term(s)	Apoptosis ; Biological Transport ; Ebolavirus/physiology ; Endosomes/metabolism ; Exosomes/virology ; Hemorrhagic Fever, Ebola/diagnosis ; Hemorrhagic Fever, Ebola/immunology ; Hemorrhagic Fever, Ebola/therapy ; Hemorrhagic Fever, Ebola/virology ; Humans ; Lymphocytes/immunology ; RNA Interference ; Viral Matrix Proteins/metabolism
Chemical Substances	VP40 protein, virus ; Viral Matrix Proteins
Language	English
Publishing date	2017-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1024454-2
ISSN	1557-7430 ; 0198-0238 ; 1044-5498
ISSN (online)	1557-7430
ISSN	0198-0238 ; 1044-5498
DOI	10.1089/dna.2017.3639
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Zs.A 2061: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Extracellular Vesicles and Ebola Virus: A New Mechanism of Immune Evasion.

Pleet, Michelle L / DeMarino, Catherine / Stonier, Spencer W / Dye, John M / Jacobson, Steven / Aman, M Javad / Kashanchi, Fatah

Viruses

2019 Volume 11, Issue 5

Abstract: Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which ... ...

Abstract	Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which transmission of the virus may occur. In acute infection, substantial cytokine storm and bystander lymphocyte apoptosis take place, resulting in uncontrolled, systemic inflammation in affected individuals. Recently, studies have demonstrated the presence of EBOV proteins VP40, glycoprotein (GP), and nucleoprotein (NP) packaged into extracellular vesicles (EVs) during infection. EVs containing EBOV proteins have been shown to induce apoptosis in recipient immune cells, as well as contain pro-inflammatory cytokines. In this manuscript, we review the current field of knowledge on EBOV EVs including the mechanisms of their biogenesis, their cargo and their effects in recipient cells. Furthermore, we discuss some of the effects that may be induced by EBOV EVs that have not yet been characterized and highlight the remaining questions and future directions.
MeSH term(s)	Animals ; Bystander Effect ; Cell Cycle ; Cytokines/metabolism ; Ebolavirus/immunology ; Ebolavirus/pathogenicity ; Exosomes/immunology ; Exosomes/metabolism ; Extracellular Vesicles/immunology ; Extracellular Vesicles/metabolism ; Hemorrhagic Fever, Ebola/immunology ; Hemorrhagic Fever, Ebola/metabolism ; Hemorrhagic Fever, Ebola/virology ; Host-Pathogen Interactions/immunology ; Humans ; Immune Evasion ; Nucleoproteins/metabolism ; Viral Core Proteins/metabolism ; Viral Matrix Proteins/metabolism
Chemical Substances	Cytokines ; Nucleoproteins ; Viral Core Proteins ; Viral Matrix Proteins ; nucleoprotein VP40, Ebola virus
Keywords	covid19
Language	English
Publishing date	2019-05-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v11050410
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Article: Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals

Sampey, Gavin C / Iordanskiy, Sergey / Pleet, Michelle L / DeMarino, Catherine / Romerio, Fabio / Mahieux, Renaud / Kashanchi, Fatah

Viruses. 2020 Sept. 23, v. 12, no. 10

2020

Abstract	Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.
Keywords	HIV infections ; Human immunodeficiency virus 1 ; animal viruses ; drugs ; manufacturing ; morbidity ; mortality ; patients ; people ; resveratrol ; therapeutics ; toxicity ; transactivators ; transcription (genetics)
Language	English
Dates of publication	2020-0923
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12101067
Database	NAL-Catalogue (AGRICOLA)

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Article: Extracellular Vesicles and Ebola Virus: A New Mechanism of Immune Evasion

Pleet, Michelle L / DeMarino, Catherine / Stonier, Spencer W / Dye, John M / Jacobson, Steven / Aman, M. Javad / Kashanchi, Fatah

Viruses. 2019 May 02, v. 11, no. 5

2019

Abstract	Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which transmission of the virus may occur. In acute infection, substantial cytokine storm and bystander lymphocyte apoptosis take place, resulting in uncontrolled, systemic inflammation in affected individuals. Recently, studies have demonstrated the presence of EBOV proteins VP40, glycoprotein (GP), and nucleoprotein (NP) packaged into extracellular vesicles (EVs) during infection. EVs containing EBOV proteins have been shown to induce apoptosis in recipient immune cells, as well as contain pro-inflammatory cytokines. In this manuscript, we review the current field of knowledge on EBOV EVs including the mechanisms of their biogenesis, their cargo and their effects in recipient cells. Furthermore, we discuss some of the effects that may be induced by EBOV EVs that have not yet been characterized and highlight the remaining questions and future directions.
Keywords	Ebolavirus ; acute course ; apoptosis ; biogenesis ; cytokines ; fever ; glycoproteins ; immune evasion ; infectious diseases ; inflammation ; nucleoproteins ; viruses ; covid19
Language	English
Dates of publication	2019-0502
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v11050410
Database	NAL-Catalogue (AGRICOLA)

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