Exosomes in the life cycle of viruses and the pathogenesis of viral infections

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Abstract

Exosomes are extracellular vesicles of endosomal origin, with a bilayer membrane, 30–160 nm in diameter. Exosomes are released from cells of different origins and are detected in various body fluids. They contain nucleic acids, proteins, lipids, metabolites and can transfer the contents to recipient cells. Exosome biogenesis involves cellular proteins of the Rab GTPase family and the ESCRT system, which regulate budding, vesicle transport, molecule sorting, membrane fusion, formation of multivesicular bodies and exosome secretion. Exosomes are released from cells infected with viruses and may contain viral DNA and RNA, as well as mRNA, microRNA, other types of RNA, proteins and virions. Exosomes are capable of transferring viral components into uninfected cells of various organs and tissues. This review analyzes the impact of exosomes on the life cycle of widespread viruses that cause serious human diseases: human immunodeficiency virus (HIV-1), hepatitis B virus, hepatitis C virus, SARS-CoV-2. Viruses are able to enter cells by endocytosis, use molecular and cellular pathways involving Rab and ESCRT proteins to release exosomes and spread viral infections. It has been shown that exosomes can have multidirectional effects on the pathogenesis of viral infections, suppressing or enhancing the course of diseases. Exosomes can potentially be used in noninvasive diagnostics as biomarkers of the stage of infection, and exosomes loaded with biomolecules and drugs - as therapeutic agents. Genetically modified exosomes are promising candidates for new antiviral vaccines.

About the authors

Alla A. Kushch

National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation

Author for correspondence.
Email: vitallku@mail.ru
ORCID iD: 0000-0002-3396-5533
SPIN-code: 6964-1715

Dr. Sci. (Biology), Professor, Leading Researcher

Russian Federation, 123098, Moscow

Alexandr V. Ivanov

Institute of Molecular Biology named after V.A. Engelhardt of Russian Academy of Sciences

Email: aivanov@yandex.ru
ORCID iD: 0000-0002-5659-9679
SPIN-code: 5776-5496

Dr. Sci. Biol., Chief Researcher, head of the laboratory of biochemistry of viral infections; deputy director for scientific work

Russian Federation, 119991, Moscow

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2. Fig. 1. Exosome biomarkers and content. In the upper half are the main markers of exosomes: membrane proteins – tetraspanins CD9, CD63, CD81 and flotillins; lipids – ceramides, components of the ESCRT system Alix и TSG101. In the lower half – viral components that are captured by exosomes in infected cells – DNA or RNA, viral structural and non-structural proteins and virions.

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3. Fig. 2. Scheme of exosome biogenesis and participation of cellular proteins of Rab family. Molecules and microparticles that penetrate into the cell by endocytosis are conventionally designated as a green triangle and a yellow circle. Rab5 participates in the fusion of endocytized vesicles to form an early endosome (EE); Rab5 and Rab4 – to the late endosome (LE); Rab1 regulates transport from the endoplasmic reticulum (ER) to the Golgi complex (GC). Rab2, on the contrary, participates in recycling and retrograde transport from GC back to ER. Rab6 regulates movements within GC. Rab7 regulates endosomal transport from LE and multivesicular bodies (MVB) to the lysosome. Rab4 and Rab11, as well as Rab 9 and Rab 25 regulate the processing of contents in recycling endosomes (RCE) and transport to the plasma membrane (PM). Rab27a and Rab35 are involved in the docking of MVB with the plasma membrane; Rab 11 and Rab35 are involved in the release of vesicles. Rab5a and Rab9a are also involved in the secretion of vesicles, enhancing the release of exosomes.

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4. Fig. 3. Schematic representation of hepatitis C virus transmission through exosomes. Exosomes containing HCV RNA in combination with microRNA (miR-122], heat shock protein HSP90 and argonaute-2 protein (Ago2) were found in the blood sera of patients with hepatitis C. Exosomes are able to penetrate uninfected cells, including hepatocytes, by endocytosis. In hepatocytes that have captured exosomes containing viral RNA, a productive HCV infection is observed, which can be transmitted through viral particles in the released exosomes. Thus, the spread of the virus is possible through exosomes, bypassing cellular receptors. NC – HCV nucleocapsid, ER – endoplasmic reticulum, GC – Golgi complex, MVB – multivesicular bodies, сосуд – vessel, экзосомы – exosomes, гепатоцит – hepatocyte, ядро – nucleus, эндоцитоз – endocytosis, экзоцитоз – exocytosis (аccording to T.N. Bukong, et al. [59]).

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5. Fig. 4. Exosomes from natural killer (NK) cells reduce the level of experimental liver fibrosis. Inactive human hepatic stellate cells of the LX-2 line were activated with TGF-β1 and then treated with exosomes isolated from NK cells – NK-Exo exosomes. As a result, human liver stellate cells activity was suppressed. The injection of NK-Exo into mice with experimentally induced fibrosis led to a decrease in the level of fibrosis. The antifibrotic effect of NK-Exo was associated with a high level of miR-223 expression directed at the autophagy protein ATG7 and suppression of its function. The blockade of autophagy caused a decrease in the level of liver fibrosis (according to L. Wang, et al. [86, 88]).

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6. Fig. 5. Exosomes in the pathogenesis of COVID-19: a – exosomes secreted by cells infected with SARS-CoV-2 are enriched with tenascin-C (TNC) and fibrinogen-β (FGB) and, penetrating into hepatocytes, initiate the production of TNF-α, IL-6 and CCL5 in hepatocytes (according to S. Sur, et al. [101]); b – exosomes containing SARS-CoV-2 genes were introduced into the culture of cardiomyocytes and the expression of viral genes and a significant increase in the expression of proinflammatory cytokines and chemokines were observed in cardiomyocytes (according to Y. Kwon, et al. [104]; c – cell receptor ACE2 interacts with the receptor-binding domain (RBD) of SARS-CoV-2 S protein, causing cell infection (left); exosomes containing ACE2 were found in the blood of patients with COVID-19. They competed with the ACE2 cell receptor, blocking the binding of S protein to cells and neutralizing the infectious activity of the virus (right) (according to L. El-Shennawy, et al. [107]); d – in the blood sera of patients with COVID-19, an increase in the number of exosomes carrying GM3 gangliosides on the surface was found. The presence of GM3-exosomes was accompanied by an increase in C-reactive protein (CRP), interleukin 6 (IL-6) and ESR rate, a decrease in the number of CD4+ cells, and also correlated with the severity of the disease (according to J.W. Song et al. [109]); e – exosomes released from endothelial cells and platelets into circulation of patients with COVID-19 contain active CD142 molecules and have increased pro-inflammatory and procoagulant activity, directly related to the severity of the disease (according to W. Holnthoner, et al. [114] and C. Balbi, et al. [115]).

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7. Fig. 6. Schematic representation of the preparation and effects of the inhaled vaccine against SARS-CoV-2. S protein SARS-CoV-2 contains a receptor binding domain (RBD). Recombinant protein RBD (rRBD) has been prepared. Human lung cells were obtained by minimal invasive biopsy and three-dimensional cultivation, from which exosomes were isolated. The exosomes were conjugated with rRBD, which was localized on the membrane of the exosome. Exosomes were injected into mice and hamsters by inhalation. In mice, the exosomal vaccine induced the induction of IgG and mucosal IgA anti–RBD antibodies, an increase in the number of CD4+ and CD8+ cells, and virus clearance after infection with SARS-CoV-2. In hamsters, the vaccine weakened severe pneumonia caused by coronavirus (Adapted with modification from Z. Wang, et al. [186]).

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