The Role of Exosomal VP40 in Ebola Virus Disease

Abstract

Ebola virus (EBOV) can cause a devastating hemorrhagic disease, leading to death in a short period of time. After infection, the resulting EBOV disease results in high levels of circulating cytokines, endothelial dysfunction, coagulopathy, and bystander lymphocyte apoptosis in humans and nonhuman primates. The VP40 matrix protein of EBOV is essential for viral assembly and budding from the host cell. Recent data have shown that VP40 exists in the extracellular environment, including in exosomes, and exosomal VP40 can impact the viability of recipient immune cells, including myeloid and T cells, through the regulation of the RNAi and endosomal sorting complexes required for transport pathways. In this study, we discuss the latest findings of the impact of exosomal VP40 on immune cells in vitro and its potential implications for pathogenesis in vivo.

Ebola Virus VP40 Modulates Cell Cycle and Biogenesis of Extracellular Vesicles

“…Alone or in conjunction with the GP and nucleoprotein (NP) of EBOV, VP40 can independently bud from cells to form virion-like particles (VLPs) that are morphologically similar to infectious virions [36][37][38][39][40][41]. Recently, we found the first evidence that VP40 is also able to exit cells by becoming packaged into exosomes [12,13]. This finding is consistent with previous studies that have shown filoviral VP40 concentrating in late endosomal compartments and multivesicular exosomal bodies [42,43].…”

“…We tested the efficacy of cdk4/6 inhibitors for their ability to hinder donor cell EV production and found that Fascaplysin and Ribociclib (Ribociclib is US Food and Drug Administration [FDA]approved) may impact the biogenesis of EVs. In previous studies, we showed that VP40 was secreted in exosomes [12,13], and here we additionally found that VP40 and other viral proteins (ie, NP and GP) were associated with EVs from wild-type EBOV-infected cells and macaques. Finally, mass spectrometry (MS) and cytokine analysis showed that exosomes originating from VP40-producing cells were enriched in several RNAbinding proteins and cytokines, which may play a pivotal role in recipient cell outcome.…”

“…There are several proposed mechanisms for the induction of apoptosis in bystander lymphocytes during EBOV pathogenesis, including the following: Fas/Fas ligand and tumor necrosis factor (TNF)-TNF-related apoptosis-inducing ligand (TRAIL) interactions, impaired dendritic cell/T-cell contacts, and nitric oxide or viral glycoprotein (GP)-induced apoptosis [5,[9][10][11]. Likewise, we have recently proposed an additional potential mechanism for the induction of bystander T-cell death in the form of the EBOV matrix protein transferred to recipient cells via exosomes [12,13]. However, the extent to which each of these mechanisms may contribute to bystander lymphocyte apoptosis and EBOV pathogenesis is not well characterized.…”

“…However, the extent to which each of these mechanisms may contribute to bystander lymphocyte apoptosis and EBOV pathogenesis is not well characterized. Nevertheless, the loss of circulating T-cell populations in infected individuals may contribute to unchecked replication of the virus, potentially correlating with poor patient prognosis [13,14].…”

“…During infection, various viral proteins and nucleic acids can become integrated into exosomes, often by utilizing the ESCRT pathway [21][22][23][24][25]. Exosomes originating from infected cells can then induce proviral effects in recipient cells [12,13,16,17,[21][22][23][24][25][26][27][28]. In addition to exosomes, other EVs such as exosome-like vesicles, microvesicles, and apoptotic bodies are produced from host cells by various mechanisms.…”