Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans
Abstract
1. Extracellular Vesicle (EV) Biogenesis
2. Isolation of EVs
2.1. Differential Centrifugation—The Gold Standard
2.2. Immunoaffinity
2.3. Density Gradient—OptiPrep™
2.4. Chromatography
2.5. Precipitation
2.6. Ultrafiltration
2.7. Nanoplasmon-Enhanced Scattering (nPES)
2.8. Lab-On-Chip Exosome Isolation
3. Exosomal Content and Characterization
4. Role of EVs in the Pathogenesis of Viral Infections
4.1. Picornaviridae and Togaviridae
4.2. Herpesviridae
4.3. Filoviridae
4.4. Paramyxoviridae
4.5. Orthomyxoviridae
4.6. Hepadnaviridae
4.7. Flaviviridae
4.7.1. ZIKA
4.7.2. EV-Mediated Restriction of ZIKV Pathogenesis
4.7.3. EV-Mediated Enhancement of ZIKV Neuropathology
4.8. Retroviridae
4.8.1. Human Immunodeficiency Virus Type 1 (HIV-1)
4.8.2. EV Interaction with Host Cell Restriction Factors and HIV
4.8.3. Immune Cell-Derived EVs and Antiviral Effects
4.8.4. EV-Mediated Enhancement of HIV-1 Infection
4.9. Coronaviridae
4.10. Polyomaviridae
5. Therapeutic Potential of EVs as Antiviral Agents
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Patdogenesis | Effect on Patdogenesis | Virus | Component | Outcome | Reference |
Picornaviridae and Togaviridae | |||||
Viral packaging within vesicles. | Enhancement | Picornaviridae | Phosphatidylserine (PS) lipid-enriched vesicles | Increased viral replication | [41,42] |
Depolymerization of the host’s actin cytoskeleton | Enhancement | Coxsackievirus B1 | Increased intracellular calcium concentration | Increased non-lytic viral spread | [43] |
Increased EV biogenesis | Enhancement | Coxsackievirus B1 | Replication competent genome within EVs | Increased viral spread | [43] |
Infectious virions hijacking apoptotic bodies | Enhancement | Chikungunya virus | Apoptotic bodies | Increased viral spread | [3] |
Herpesviridae | |||||
miRNA and mRNA are transported via exosomes | Enhancement | HSV-1 | Exosome-bound miRNA and mRNA | Suppressed viral reactivation, facilitating viral transmission to new host | [44] |
EV-bound MHC-II activates CD4+ T-cells | Inhibition | EBV | EVs derived from EBV infected B-lymphocytes | Potentially activate CD4+ T- lymphocytes | [6,38] |
Transport of immunoregulator protein galectin-9, a CD4+ T-cell apoptosis inducer | Enhancement | EBV | EBV-infected nasopharyngeal carcinoma cell-derived exosome-bound immunoregulator protein galectin-9 | Increased evasion of host immune response | [6,46,47] |
Inhibition of Natural Killer (NK) cell cytotoxicity, IFN-γ production, and T-lymphocyte activation and proliferation by LMP1 | Enhancement | EBV | EV-bound LMP1 | Increased evasion of host immune response | [6,46,48,49] |
Filoviridae | |||||
Transportation of VP40 into the cell nucleus and subsequent binding of VP40 to cyclin D1′s promoter | Enhancement | EBOV | VP40-laden exosomes | Facilitates the regulation of EV synthesis via over-transcription of cyclin D1, dysregulating the cell cycle. | [52] |
Transportation of VP40 into the cell nucleus | Enhancement | EBOV | VP40-laden exosomes | Exerts a dose-dependent decrease in cellular viability of recipient monocytes and T-cells | [52] |
Modulation of RNAi machinery, such as Dicer and Ago 1 | Enhancement | EBOV | VP40-laden exosomes | Inducing cell death of recipient naïve cells while upregulating exosome biogenesis. | [54] |
Paramyxoviridae | |||||
RSV infection upregulated expression of select exosome-bound miRNA and piRNA content | Enhancement | RSV | Exosomes generated from RSV infected A549 cells | Increased exosomal miRNA and piRNA content | [55] |
Exposure of PBMC-isolated human monocytes to exosomes derived from RSV infected cells | Enhancement | RSV | Exosomes generated from RSV infected A549 cells | Induced the secretion of proinflammatory mediators, such as IP-10, RANTES, and MCP-1 | [55] |
Orthomyxoviridae | |||||
Intercellular communication via exosomal miRNAs | Enhancement | IAVs | Exosomes generated from IAV infected cells | Modulate cell function, alter recipient cell pathways, facilitate viral persistence, and alter circulating miRNAs | [58,59,60,61,62,63] |
Exosomes containing miRNA hsa-miR-1975 | Enhancement | IAVs | IAV-infected human lung adenocarcinoma epithelial A549 cell-derived exosomes | inhibit IAV replication by inducing interferon production | [64] |
The transportation to the apical side of the membrane of IAV progeny RNA by attaching to Rab11 vesicles | Enhancement | IAVs | Exosomes generated from IAV infected cells | Facilitating late stage IAV budding and infection | [6,66] |
IAVs integrate exosomal proteins or markers such as Annexin A3, CD9, CD81, and ICAM1 | Enhancement | IAVs | Exosomes generated from IAV infected cells | Contribution to the influenza virion structure, viral spread | [67] |
Hepnaviridae | |||||
HBV HBx protein-mediated host gene stimulation, cell cycle interference, and mitogenic signaling | Enhancement | HBV | HBx protein and mRNA encapsulated within exosomes | Permits horizontal transfer of its gene products, expression of viral protein, and facilitates oncogenic activities | [68] |
Inducing proliferative signaling and enhancing exosome biogenesis via increasing neutral sphingomyelinase 2 activity | Enhancement | HBV | HBx protein and mRNA encapsulated within exosomes | Altered exosomal cargo (quantitatively and qualitatively) and promote HBV-associated liver diseases | [68] |
Induce mRNA expression of the NKG2D ligand in macrophages | Inhibition | HBV | Exosomes generated from HBV infected cells and which contain viral RNA | NK cell activation, confirmed by CD69 upregulation, and induction of IFN-γ production promoting innate immunity and lymphocyte activation to defend the host from infections | [69,70] |
Infection with HBV | Enhancement | HBV | Exosomes generated from HBV infected cells | An increase in immunosuppressive miRNAs: miR-21 and miR-29a, within CD81+ exosomes, transferred from hepatocytes to macrophages | [69] |
Downregulation of IL-12p35 and IL-12p40 | Enhancement | HBV | Exosomes generated from HBV infected cells and containing immunosuppressive miRNAs: miR-21 and miR-29a | Potential inhibition of NK cell activity and facilitation of viral evasion of the host immune response | [69] |
HBV modulation of exosome-bound proteins, including the increase of 5 proteasome subunit proteins: PSMD1, PSMD7, PSMD14, PSMC1, and PSMC2, enhancing proteolytic activity | Enhancement | HBV | 35 exosome-bound proteins quantitatively altered as a result of HBV infection in HBV-infected HepAD38 hepatoblastoma cell line-derived exosomes | Significant reducing monocyte IL-6 production and modulation of proinflammatory molecules | [71] |
Uptake of these HBV-laden exosomes by cells | Enhancement | HBV | HBV-laden exosomes | Impairment of NK cell production of IFN-γ, NK cell survival and proliferation, cytolytic activity, and NK cell responsiveness to stimulation from poly (I:C) | [72] |
Antiviral activity has been observed to be transferred from liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes | Inhibition | HBV | LNPC-derived exosomes | IFN-α induced HBV antiviral activity | [73] |
Flaviviridae | |||||
Viral packaging within vesicles. | Enhancement | HCV | Exosome-bound viral particles | Increased viral spread. Activate immune cells and establish infection | [74,75] |
Transportation of viral regulatory elements: Human Ago2 and miR-122 | Enhancement | HCV | Exosome-bound Ago2 and miR-122 | Increased viral spread | [74,76] |
Infected-tick cell-derived EVs mediate transmission of viral RNA and NS1 protein | Enhancement | LGTV | Exosome-bound viral RNA and NS1 | Increased transmission from arthropod vectors to humans. Disseminate virus within host neuronal cells. | [31,77] |
Transfer of antiviral properties from EVs carrying C19MC miRNAs | Inhibition | ZIKV | EV-bound C19MC miRNAs | Increased autophagy and viral resistance. Decreased ZIKV viral replication. | [83,84] |
Downregulation of miR-21 after exposure to EVs | Inhibition | ZIKV | Infected HPT cell-derived EVs | Decreased TLR7-mediated neurotoxicity | [87,88] |
Exposure of placental cells to EVs | Enhancement | ZIKV | Macrophage-derived exosomes | Induction of placental proinflammatory cytokine production. | [91] |
Stimulation of human macrophage IL-1β secretion | Enhancement | ZIKV | ZIKV NS5-mediated activation of NLRP3 | Activation of host inflammatory response and macrophage recruitment promotes inflammation | [92] |
EVs transmitted across neurons | Enhancement | ZIKV | EV-bound ZIKV-RNA and E-protein | Increased ZIKV transmission across neurons | [93] |
Modulation of SMPD3 activity as a result of ZIKV cortical neuron infection | Enhancement | ZIKV | EV-bound SMPD3 | Increased EV biogenesis, viral burden, and viral transmission | [93] |
Retrovirdae | |||||
Release of HIV-1 infected cell-derived EVs | Enhancement | HIV | gp120 laden HIV-1 envelope (Env) protein | Increased HIV-1 infectivity in lymphoid tissues | [119,120,121,122] |
Increased EV-mediated Nef egress | Enhancement | HIV | EV-bound Nef protein | Increased EV secretion, presence of MVBs within cells, decay of CD4+ T-cell populations | [123,124,125,126] |
Transport of Nef via exosomes to target cells | Enhancement | HIV | EV-bound Nef protein | Promote decay of CD4+ T-cell populations, promote CD8+ T-cell activity, CXCR4-mediated apoptosis, and ADAM17 activation increasing CD4+ T-cell permissiveness to HIV-1 | [127,128,129,130] |
Differential miRNA content relative to uninfected cells | Enhancement | HIV | HIV-1 co-evolution with the host | Facilitating suppression of host RNA interference (RNAi) | [131,137] |
Release of HIV-1 infected plasma and macrophage derived EVs | Enhancement | HIV | HIV-1-derived miRNAs, vmiR88 and vmiR99 | Promoting macrophage release of TNF-α, thus supporting chronic immune activation | [138] |
Modulation of exosomal and cellular miRNA profiles | Enhancement | HIV | EV-bound Nef protein | Modulation of HIV-1 pathogenesis and viral replication | [139] |
Reduced ZO-1 TJ protein expression in HBMECs and increasing TLR-induced chemokines and cytokines in microglia | Enhancement | HIV | Microglia-derived EV-bound Nef | Disruption of BBB permeability and integrity | [141] |
Coronaviridae | |||||
Uptake of these SARS-CoV-2 exosomes by human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) | Enhancement | SARS-CoV-2 | SARS-CoV-2 infected cell-derived exosomes | Upregulation of genes associated with inflammation in hiPSC-CM | [133] |
Delivery of viral RNA packaged within exosomes | Enhancement | SARS-CoV-2 | SARS-CoV-2 infected cell-derived exosomes | Indirect infection of target cardiomyocytes, exacerbating pathology, and altering the inflammatory state | [134] |
Incorporation of spike S protein into exosomes and priming with the S-protein exosome vaccine with subsequent boosting via addition of adenoviral vector vaccine | Inhibition | SARS-CoV-2 | Vaccine: Exosomes incorporated with spike S proteins | Generation of neutralizing antibodies titers exceeding those of a SARS-convalescent patient serum | [136,142] |
Pathogenesis | Component | Outcome | Component | Outcome | Reference |
Retrovirdae | |||||
CD8+ T-cell derived exosome transport | Inhibition | HIV | Membrane bound anti-HIV protein moiety | Decreased HIV-1 replication | [101] |
Transport of antiviral factors at both the protein and mRNA level | Inhibition | HIV | TLR3-activated HBMEC-derived exosomes-bound antiviral factors | Block HIV-1 infection to the CNS. Transferring anti-HIV protection to macrophages | [102] |
Release of TLR3-activated IEC-derived exosomes containing anti-HIV-1 factors | Inhibition | HIV | HIV-restriction miRNAs (miRNA-20 and miRNA125b), and IFN-stimulated genes (ISGs: ISG15, OAS-1, and Viperin) | Increased Anti-HIV GI innate immunity | [103] |
Blocking viral reverse transcription | Inhibition | HIV | Vaginal fluid-derived EVs | Post-entry block of HIV-1 replication | [105] |
Deleterious effects upon HIV-1 reverse transcriptase activity | Inhibition | HIV | Non-infected semen-derived EVs | Post-entry block of HIV-1 replication | [105,106] |
Viral packaging within vesicles. | Enhancement | HIV | Semen-derived EV-bound functional viral mRNA | Increased viral spread | [105] |
Binding to DC-SIGN receptor, competing with HIV-1 | Inhibition | HIV | Uninfected donor breast milk-derived EVs | Decreased HIV-1 infection of DC and viral transfer to CD4+ T-lymphocytes | [107] |
Transport of PBMC-derived EVs to neighboring cells deficient in CCR5 | Enhancement | HIV | PBMCs-derived EVs containing CCR5 | Enhanced cellular susceptibility to HIV-1 | [109] |
Delivering the HIV-1 co-receptor to nearby tissues lacking CXCR4 expression | Enhancement | HIV | Megakaryocyte-derived EVs containing CXCR4 | Facilitates viral spread | [110,111] |
Transport of EVs to endothelial cells and PBMCs deficient in CCR5 | Enhancement | HIV | PBMC-derived EV-encapsulated CCR5 chemokine receptors | Enhancing HIV-1 infection | [109] |
Transport of EVs to cells deficient in CXCR4 | Enhancement | HIV | Megakaryocyte and platelet-derived EV-encapsulated CXXR4 receptors | Enhancing HIV-1 infection | [110,111] |
Binding of EV-bound TIM-4 to HIV-1 PS surface-bound moieties | Enhancement | HIV | EV-bound TIM4 receptor | Increased exosome-mediated trafficking of HIV-1 to human immune cells | [112,113] |
HIV-1 Entrapping itself with exosome aggregates via exploitation of exosomal surface properties | Enhancement | HIV | Exosomal surface properties | Host-immune system evasion via camouflage. Increased viral spread | [116] |
Exposure of EVs to macrophages yield a significant rise in proinflammatory cytokines, TNF-β, and IL-6 | Enhancement | HIV | HIV-1 infected primary cell-derived EV-bound TAR | Enhance undifferentiated naïve cell susceptibility to HIV-1 infection | [117] |
DC-CD44 receptor binding of apoptotic microvesicles | Enhancement | HIV | Apoptotic body-bound DC-CD44 receptor | Decreased DC-dependent cytokine production and inhibition of DC-mediated T/NK-cell priming | [3] |
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Caobi, A.; Nair, M.; Raymond, A.D. Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans. Viruses 2020, 12, 1200. https://doi.org/10.3390/v12101200
Caobi A, Nair M, Raymond AD. Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans. Viruses. 2020; 12(10):1200. https://doi.org/10.3390/v12101200
Chicago/Turabian StyleCaobi, Allen, Madhavan Nair, and Andrea D. Raymond. 2020. "Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans" Viruses 12, no. 10: 1200. https://doi.org/10.3390/v12101200
APA StyleCaobi, A., Nair, M., & Raymond, A. D. (2020). Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans. Viruses, 12(10), 1200. https://doi.org/10.3390/v12101200