Extracellular Vesicles in Viral Infections: Two Sides of the Same Coin?

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.

Why Cells and Viruses Cannot Survive without an ESCRT

“…Exosomes are the smallest subclass of EVs with a diameter ranging from 30 to 120 nm. In addition to the Alix-mediated mechanisms, also classical ESCRT-I/ESCRT-IIdependent engagement of ESCRT-III has been described in exosome formation, as well as ESCRT machinery-independent processes [8]. Exosomes play a key role in cell-to-cell signaling and are emerging as important tools for diagnosis/treatment of diseases, cancer included, and as prognostics markers.…”

“…Exosomes play a key role in cell-to-cell signaling and are emerging as important tools for diagnosis/treatment of diseases, cancer included, and as prognostics markers. Indeed, their cargo, which encompasses not only proteins but also lipids and nucleic acids, such as micro-ribonucleic acids (miRNAs) and long non-coding RNAs (lncRNAs), as well as functional messenger RNAs (mRNAs), is protected and can be delivered to target cells or quantified upon vesicle harvesting [8].…”

“…We mention the involvement of autophagy in viral transmission later. As far as EVs are concerned, it is interesting to note that they can act both as promoters or inhibitors of viral spreading and infection [8,133]. This dual effect is well exemplified by EVs released from human immunodeficiency virus type 1 (HIV-1)-infected cells.…”

“…As the healthy counterpart, virus infected cells can secrete EVs that can exert different functions as described above. These EVs can shed viral proteins, and nucleic acids and either trigger immune responses or affect recipient cells, favoring viral spreading [8]. Interestingly, EVs and enveloped viral particles share common biogenesis machinery, and in some cases, it is difficult to isolate EVs containing viral molecules from forms of defective viral particles as they display similar density, size, and composition [8].…”

“…Finally, EVs play a broad-spectrum role in the pathogenesis of viral infection. Indeed, viruses not only adopt exosomes to accomplish specific steps of their life cycle, but also exploit these EVs to transfer both viral and cellular factors, such as proteins and non-coding RNAs, outside the infected cells to promote infection and to escape from the immune system [8].…”