Uveitis and Systemic Inflammatory Markers in Convalescent Phase of Ebola Virus Disease

Chancellor, John R.; Padmanabhan, Sriranjani; Greenough, Thomas C.; Sacra, Richard; Ellison, Richard T.; Madoff, Lawrence C.; Droms, Rebecca; Hinkle, David M.; Asdourian, George K.; Finberg, Robert W.; Ströher, Ute; Uyeki, Timothy M.; Cerón, Olga

doi:10.3201/eid2202.151416

Cited by 30 publications

(28 citation statements)

References 11 publications

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“…Despite clearance of virus from the blood, EBOV is able to persist in immunologically protected sites in the body, including ocular fluid, semen, and vaginal fluids, as well as in sweat, urine, and breast milk (Deen et al, 2015; Varkey et al, 2015; Chancellor et al, 2016; Harries et al, 2016; MacIntyre and Chughtai, 2016). A recent study of survivors in Sierra Leone showed that EBOV may persist for much longer than previously recognized, with over 1 in 4 male EBOV survivors containing virus in their semen for up to 7–9 months post disease onset (Deen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction

et al. 2016

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Ebola virus (EBOV) is an enveloped, ssRNA virus from the family Filoviridae capable of causing severe hemorrhagic fever with up to 80–90% mortality rates. The most recent outbreak of EBOV in West Africa starting in 2014 resulted in over 11,300 deaths; however, long-lasting persistence and recurrence in survivors has been documented, potentially leading to further transmission of the virus. We have previously shown that exosomes from cells infected with HIV-1, HTLV-1 and Rift Valley Fever virus are able to transfer viral proteins and non-coding RNAs to naïve recipient cells, resulting in an altered cellular activity. In the current manuscript, we examined the effect of Ebola structural proteins VP40, GP, NP and VLPs on recipient immune cells, as well as the effect of exosomes containing these proteins on naïve immune cells. We found that VP40-transfected cells packaged VP40 into exosomes, and that these exosomes were capable of inducing apoptosis in recipient immune cells. Additionally, we show that presence of VP40 within parental cells or in exosomes delivered to naïve cells could result in the regulation of RNAi machinery including Dicer, Drosha, and Ago 1, which may play a role in the induction of cell death in recipient immune cells. Exosome biogenesis was regulated by VP40 in transfected cells by increasing levels of ESCRT-II proteins EAP20 and EAP45, and exosomal marker proteins CD63 and Alix. VP40 was phosphorylated by Cdk2/Cyclin complexes at Serine 233 which could be reversed with r-Roscovitine treatment. The level of VP40-containing exosomes could also be regulated by treated cells with FDA-approved Oxytetracycline. Additionally, we utilized novel nanoparticles to safely capture VP40 and other viral proteins from Ebola VLPs spiked into human samples using SDS/reducing agents, thus minimizing the need for BSL-4 conditions for most downstream assays. Collectively, our data indicates that VP40 packaged into exosomes may be responsible for the deregulation and eventual destruction of the T-cell and myeloid arms of the immune system (bystander lymphocyte apoptosis), allowing the virus to replicate to high titers in the immunocompromised host. Moreover, our results suggest that the use of drugs such as Oxytetracycline to modulate the levels of exosomes exiting EBOV-infected cells may be able to prevent the devastation of the adaptive immune system and allow for an improved rate of survival.

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Section: Introductionmentioning

confidence: 99%

Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction

et al. 2016

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“…Viral persistence has been documented in other compartments as well, including the eyes, brain, breast milk, and vaginal secretions (Rodriguez et al, 1999;Varkey et al, 2015;Billioux et al, 2016;Chancellor et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The Role of Exosomal VP40 in Ebola Virus Disease

Pleet

DeMarino

Lepene

et al. 2017

DNA and Cell Biology

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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.

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“…Recently published studies highlight the occurrence of post-EVD complications, such as uveitis ( 2 , 3 ) and encephalopathy ( 4 ), but these are isolated investigations. Evidence on the prevalence of these and other sequelae is increasing.…”

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confidence: 99%

“…Many survivors also face EVD-related stigma and rejection from their communities ( 5 , 8 ) and suffer with posttraumatic stress disorder, depression, or anxiety ( 5 , 7 – 9 ). Furthermore, new ocular problems, such as uveitis, are commonly reported among survivors ( 2 , 5 , 6 , 10 ). A summary of the literature on these sequelae was presented in a recently published review article, but evidence from the 2014–15 West Africa outbreak had a maximum duration of follow-up of 1 year ( 11 ).…”

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confidence: 99%