Ebola Virus VP40 Modulates Cell Cycle and Biogenesis of Extracellular Vesicles

Abstract

Nuclear VP40 upregulates cyclin D1 levels, resulting in dysregulated cell cycle and EV biogenesis. Packaging of cytokines and EBOV proteins into EVs from infected cells may be responsible for the decimation of immune cells during EBOV pathogenesis.

Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans

“…Infection with the ssRNA, negative sense Ebola virus (EBOV) results in systemic infection with severe hemorrhagic fever, immune suppression or overactivation, and tissue damage [ 37 , 38 , 39 ]. Upon infection, EBOV primarily targets dendritic cells, monocytes, and macrophages, potentially facilitating systemic virus spread, including liver and secondary lymphoid organs [ 40 ].…”

“…Given the symptoms mentioned above and the high mortality rate of 80–90%, Ebola patients’ rapid identification is necessary [ 41 ]. A commonly applied technique for diagnosing Ebola patients is the detection of VP40, the EBOV matrix protein [ 39 ]. VP40 may employ two methods to release from cells, independent budding from cells or exosomal incorporation [ 39 ].…”

“…A commonly applied technique for diagnosing Ebola patients is the detection of VP40, the EBOV matrix protein [ 39 ]. VP40 may employ two methods to release from cells, independent budding from cells or exosomal incorporation [ 39 ]. This transportation of VP40 into the nucleus facilitates EV synthesis regulation via over-transcription of cyclin D1 by binding VP40 to cyclin D1′s promoter, dysregulating the cell cycle [ 39 ].…”

“…VP40 may employ two methods to release from cells, independent budding from cells or exosomal incorporation [ 39 ]. This transportation of VP40 into the nucleus facilitates EV synthesis regulation via over-transcription of cyclin D1 by binding VP40 to cyclin D1′s promoter, dysregulating the cell cycle [ 39 ]. Additionally, the VP40-laden exosomes exert a dose-dependent decrease in cellular viability of recipient monocytes and T-cells; and these exosomes contained cytokines, which may contribute to EBOV pathology [ 39 ].…”

Autophagy, EVs, and Infections: A Perfect Question for a Perfect Time

“…It is believed that in some of these cases, such as with HIV and herpesviruses, that these viruses allow the release of exosomes containing viral components to prime distant recipient cells, which thereby enhances their susceptibility to infection (Chahar et al, 2015 ; Anderson et al, 2016 ; Sampey et al, 2016 ; Raab-Traub and Dittmer, 2017 ). On the other hand, the packaging of viral components into exosomes also may mediate recipient cell damage and death, particularly in immune or CNS-resident cells, such as in the cases of EBOV and HIV (Lenassi et al, 2010 ; Pleet et al, 2016 , 2018 ). It has also been shown that exosomes released from hepatitis A virus and hepatitis C virus-infected cells have the potential to spread virions that are capable of directly infecting recipient cells (Fleming et al, 2014 ).…”