Abstract
Extracellular vesicles (EVs), released by cells, are associated with cell-to-cell communication and regulate various cellular processes. EVs draw parallels with viruses for their similar structures and functions. Increasing evidences from recent studies indicate that cells infected with viruses release a variety of EVs. Delineating the functions and mechanisms of EVs released during virus infection is essential for understanding the molecular basis of viral infection and replication as well as associated pathogenesis. The most challenging obstacle for these studies is the separation of EVs from viruses. In this study, we successfully isolated the EVs from de novo Kaposi’s sarcoma-associated herpesvirus (KSHV) infected-human endothelial cells during the period between virus entry and production. Intriguingly, a proteomics analysis of these EVs has revealed alterations of the complement system. Additionally, we have discovered that the EVs from KSHV-infected endothelial cells are potent activators of an alternative pathway of the complement system via exploitation of the endogenous C3 complement protein and properdin. Furthermore, we have found that complement activation promotes KSHV persistent latent infection by activating the NF-κB pathway, which enhances the survival of KSHV-infected cells and inhibits viral lytic replication. Our work identifies a novel role of EVs induced by KSHV during de novo infection and the underlying mechanism of complement activation by EVs.
Highlights
Extracellular vesicles (EVs) are membraneenclosed vesicles released by cells and play a role in cell-to-cell communication during various physiological and pathological processes, including inflammation and cancer [1, 2]
Electron microscopy revealed that most of the isolated EVs were around 30–40 nm, which were much smaller than Kaposi’s sarcoma-associated herpesvirus (KSHV) particles, and were free of KSHV particles (Figure 1A)
Our results indicated that EVs were successfully isolated from the supernatant of de novo KSHV-infected human endothelial cells without any contamination of virions
Summary
Extracellular vesicles (EVs) are membraneenclosed vesicles released by cells and play a role in cell-to-cell communication during various physiological and pathological processes, including inflammation and cancer [1, 2]. EVs contain a high concentration of RNAs, proteins, DNA, microRNAs, and bioactive lipids. EVs can be taken up by the surrounding cells to regulate multiple biological processes, their precise roles are still not fully understood [3]. Viruses share the cellular vesiculation machinery with EVs [5], both of which have similar lipid composition and protein content. Because of their common biogenesis paths, viruses and EVs may be close relatives and the production of EVs could be altered during virus infection and production.
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