Cerebrospinal Fluid Examination in Survivors of Ebola Virus Disease

Billioux, Bridgette Jeanne; Nath, Avindra; Stavale, Eric; Dorbor, Joseph; Fallah, Mosoka; Sneller, Michael C.; Smith, Bryan

doi:10.1001/jamaneurol.2017.1460

Cited by 15 publications

(13 citation statements)

References 3 publications

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“…EBOV infection of the supporting cells of the peripheral ganglia and nerves, with attendant inflammation, is intriguing, as the nature of neurologic impairment in EVD survivors is hotly debated 17 , 26 , 44 , 45 . Damage to these neural supporting cells, with a pro-inflammatory resolution, could conceivably lead to long-term nerve or ganglion damage, manifesting as altered sensory inputs or dysautonomia.…”

Section: Discussionmentioning

confidence: 99%

Histology, immunohistochemistry, and in situ hybridization reveal overlooked Ebola virus target tissues in the Ebola virus disease guinea pig model

Cooper

Huzella

Johnson

et al. 2018

Sci Rep

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Survivors of Ebola virus infection may become subclinically infected, but whether animal models recapitulate this complication is unclear. Using histology in combination with immunohistochemistry and in situ hybridization in a retrospective review of a guinea pig confirmation-of-virulence study, we demonstrate for the first time Ebola virus infection in hepatic oval cells, the endocardium and stroma of the atrioventricular valves and chordae tendinae, satellite cells of peripheral ganglia, neurofibroblasts and Schwann cells of peripheral nerves and ganglia, smooth muscle cells of the uterine myometrium and vaginal wall, acini of the parotid salivary glands, thyroid follicular cells, adrenal medullary cells, pancreatic islet cells, endometrial glandular and surface epithelium, and the epithelium of the vagina, penis and, prepuce. These findings indicate that standard animal models for Ebola virus disease are not as well-described as previously thought and may serve as a stepping stone for future identification of potential sites of virus persistence.

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Section: Discussionmentioning

confidence: 99%

Histology, immunohistochemistry, and in situ hybridization reveal overlooked Ebola virus target tissues in the Ebola virus disease guinea pig model

Cooper

Huzella

Johnson

et al. 2018

Sci Rep

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“…The observations in this study on the detection of HTLV-1 viral antigens in exosomes found in virus-free CSF supernatant has implications for other virally associated neuroinflammatory diseases. For example, Ebola virus has been shown to be associated with long-term neurologic sequelae even though the virus is thought to have been cleared [ 81 , 82 ], and while Ebola viral proteins have been detected within exosomes in vitro [ 83 ], this has not yet been shown to be the case within patient CSF material. As we have demonstrated that HAM/TSP CSF supernatant, which is HTLV-1 negative, contains HTLV-1 Tax + exosomes, exosomes containing viral antigens could be a potential biomarker for neurologic disorders associated with viral infections in which the virus may be absent in CSF.…”

Section: Discussionmentioning

confidence: 99%

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Anderson

Pleet

Enose-Akahata

et al. 2018

Clinical & Translational Med

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Background HTLV-1 infects over 20 million people worldwide and causes a progressive neuroinflammatory disorder in a subset of infected individuals called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The detection of HTLV-1 specific T cells in the cerebrospinal fluid (CSF) suggests this disease is immunopathologically mediated and that it may be driven by viral antigens. Exosomes are microvesicles originating from the endosomal compartment that are shed into the extracellular space by various cell types. It is now understood that several viruses take advantage of this mode of intercellular communication for packaging of viral components as well. We sought to understand if this is the case in HTLV-1 infection, and specifically if HTLV-1 proteins can be found in the CSF of HAM/TSP patients where we know free virus is absent, and furthermore, if exosomes containing HTLV-1 Tax have functional consequences. Results Exosomes that were positive for HTLV-1 Tax by Western blot were isolated from HAM/TSP patient PBMCs (25/36) in ex vivo cultures by trapping exosomes from culture supernatants. HTLV-1 seronegative PBMCs did not have exosomes with Tax (0/12), (Fisher exact test, p = 0.0001). We were able to observe HAM/TSP patient CSF (12/20) containing Tax + exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant (Fisher exact test p = 0.0391). Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis. Conclusion Cumulatively, these results show that there are HTLV-1 proteins present in exosomes found in virus-free CSF. HAM/TSP PBMCs, particularly CD4 + CD25 + T cells, can excrete these exosomes containing HTLV-1 Tax and may be a source of the exosomes found in patient CSF. Importantly, these exosomes are capable of sensitizing an HTLV-1 specific immune response, suggesting that they may play a role in the immunopathology observed in HAM/TSP. Given the infiltration of HTLV-1 Tax-specific CTLs into the CNS of HAM/TSP patients, it is likely that exosomes may also contribute to the continuous activation and inflammation observed in HAM/TSP, and may suggest future targeted therapies in this disorder. Electronic supplementary material The online version of this article (10.1186/s40169-018-0204-7) contains supplementary material, which is available to authorized users.

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“…The observation of common neurological sequelae in survivors of recent filovirus outbreaks has reignited the debate about whether these observed clinical signs are a direct result of neuronal infection or are a by-product of antiviral immune responses. The demonstration of infectious virus in the CSF of patients is a clear indication that the virus is capable of entering and replicating within the immunoprivileged locale of the CNS (8, 15, 21). The demonstration of viral persistence in other immunoprivileged sites, such as the eye and testes, also raises the question of viral persistence in the CNS (23, 26, 50, 51).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent to the initial Marburg virus outbreaks, most symptomatic human filovirus infections occurred in remote communities in Africa, in countries without efficient medical infrastructure and a small number of survivors with minimal opportunities for follow-up. A recent large-scale Ebola virus outbreak in West Africa has permitted the tracing of survivors and have allowed for the determination of longer-term effects of Ebola virus infection in humans (8–20). These long-term sequelae include a range of neurological and psychological disorders, including headache, fatigue, depression, meningoencephalitis, and cerebral and/or cerebella atrophy (8–10, 12–17, 19, 20).…”

Section: Introductionmentioning

confidence: 99%

“…Due to the risk and complexities associated with the collection of anatomical samples from Ebola patients, analysis of brain material from infected individuals has not been possible. However, a number of studies have demonstrated the presence of infectious virus within the cerebrospinal fluid (CSF) of Ebola survivors, months after initial discharge from hospital (8, 15, 21). In addition, there have been numerous reports of ocular involvement following Ebola virus disease, leading to persistent infection (22–26).…”

Section: Introductionmentioning

confidence: 99%

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Filoviruses Can Efficiently Infect Human Neuron-Like Cells Without Genetic Adaptation

McAuley

Tachedjian

Marsh

2019

Preprint

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7 Recent large-scale Ebola outbreaks, combined with improved follow-up of survivors, has 8 permitted the observation of common long-term neurological sequelae in patients that have 9 survived Ebola virus infection. To date there have been few studies into neurological 10 infections by Ebola or related filoviruses, however, recent studies have isolated infectious 11 virus from patients' cerebrospinal fluid months after being discharged from the treatment 12 facility. 13 14 In order to determine whether different filoviruses were capable of infecting human 15 neurons, the human neuroblastoma cell lines, SH-SY5Y and M17, were chemically-16 differentiated into more neuron-like cells using established protocols. The neuron-like 17 profiles of the differentiated cells were confirmed by the determination of expression of a 18 range of neuron-specific markers. Zaire ebolavirus, Reston ebolavirus, and Marburg virus 19 were serially-passaged in both cell lines to determine permissiveness of the cells, as well as 20 permit the acquisition of adaptive mutations in the viral genomes. Whilst Marburg virus 21 grew to high titres in both cell lines, Zaire ebolavirus only grew in SH-SY5Y cells, and Reston 22 ebolavirus rapidly died out in both cell lines. Whole-genome sequencing of the passaged 23 viruses revealed two consensus-level non-coding mutations in the SH-SY5Y-passaged 24 Marburg virus. Viral growth kinetics were determined for pre-and post-passaging Zaire 25 ebolavirus and Marburg virus in both human neuronal cell lines, as well as the human 26 hepatocyte cell line, Huh7. Growth kinetics were similar for both the pre-and post-passaged 27 viruses, suggesting that adaptive mutations were not required for efficient growth in these 28 cells.29 30 This study is the first to demonstrate that filoviruses are capable of infecting human neuron-31 like cells in a species-specific manner. Marburg virus-infected cells remained alive up to Day 32 21 post-infection, suggesting that long-term neurological sequelae following filovirus 33 infection may be a result of direct neuronal infection, and that infection of neurons might 34 contribute to viral persistence in survivors. 3536 Author Summary 37 Filoviruses, including Ebola and Marburg viruses, have been traditionally considered 38 "haemorrhagic fever" viruses, with infections causing bleeding and frequently death. Recent 39 large-scale outbreaks in Africa have challenged these assumptions due to a significant 40 number of patients reporting neurological symptoms sometimes months after infection. In 41 many of these patients, virus was present at detectable levels in the fluid surrounding the 42 brain. There has been significant debate about the ability of Ebola and Marburg viruses to 43 infect and grow in human neurons (brain cells), and evidence has been lacking due to the 44 lack of feasibility in taking brain samples. Our study demonstrates that both Zaire ebolavirus 3 45 and Marburg virus are capable of infecting cells derived from human brains without needing 46 to change, and...

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Cerebrospinal Fluid Examination in Survivors of Ebola Virus Disease

Abstract: Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Cited by 15 publications

References 3 publications

Histology, immunohistochemistry, and in situ hybridization reveal overlooked Ebola virus target tissues in the Ebola virus disease guinea pig model

Histology, immunohistochemistry, and in situ hybridization reveal overlooked Ebola virus target tissues in the Ebola virus disease guinea pig model

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

Filoviruses Can Efficiently Infect Human Neuron-Like Cells Without Genetic Adaptation

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