scholarly journals VSV-EBOV Induces Temporal and Dose-Dependent Transcriptional Responses in Non-human Primates

2021 ◽  
Vol 1 ◽  
Author(s):  
Amanda N. Pinski ◽  
Kevin J. Maroney ◽  
Andrea Marzi ◽  
Ilhem Messaoudi
Keyword(s):  
Cell Activation ◽  
Ebola Virus ◽  
Virus Disease ◽  
Lethal Dose ◽  
Transcriptional Analysis ◽  
B Cell Activation ◽  
Transcriptional Responses ◽  
Transcriptional Signature ◽  
Before And After ◽  
Ebov Infection

Zaire Ebola virus (EBOV), the causative agent of Ebola virus disease (EVD), is a member of the Filoviridae family. EVD is characterized by innate and adaptive immune dysregulation that leads to excessive inflammation, coagulopathy, lymphopenia, and multi-organ failure. Recurrent outbreaks of EBOV emphasize the critical need for effective and deployable anti-EBOV vaccines. The FDA-approved VSV-EBOV vaccine protects non-human primates (NHPs) and humans from EBOV when given at a 10–20 million PFU dose. We recently demonstrated that a dose as small as 10 PFU protected NHPs from lethal EBOV infection. Furthermore, 1 PFU of VSV-EBOV protected 75% of vaccinated NHPs. In this study, we performed a comparative transcriptional analysis of the whole blood transcriptome in NHPs vaccinated with doses of VSV-EBOV associated with complete protection (10M PFU), protection with mild EVD (10 PFU), and break-through protection (1 PFU) before and after challenge with a lethal dose of EBOV Makona. Transcriptional findings demonstrated that, regardless of dose, vaccination significantly attenuated the upregulation of genes associated with fatal EVD. Genes involved in T- and B-cell activation were more highly expressed in groups receiving 10 or 10M PFU than in 1 PFU–vaccinated animals. Furthermore, the singular vaccinated (1 PFU) non-survivor exhibited a transcriptional signature distinct from both surviving vaccinated animals and controls that received an irrelevant vaccine. These findings provide additional insight into mechanisms of vaccine-mediated protection and informing public policy on vaccine distribution during outbreaks.

scholarly journals Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Mike Flint ◽  
Éric Bergeron ◽  
Anita K. McElroy ◽  
Payel Chatterjee ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Statin Treatment ◽  
Ebola Virus Disease ◽  
Health Concern ◽  
Virus Infectivity ◽  
Viral Glycoprotein ◽  
Antiviral Effects ◽  
Ebov Infection ◽  
Glycoprotein Processing

ABSTRACTEbola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infectionin vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCETreatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

Characterization of an Anti-Ebola virus Hyperimmune Globulin Derived from Convalescent Plasma

2021 ◽  
Author(s):  
Jonathan M Ciencewicki ◽  
Andrew S Herbert ◽  
Nadia Storm ◽  
Nicole M Josleyn ◽  
Kathleen Huie ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Fold Increase ◽  
Surface Glycoprotein ◽  
Post Exposure Prophylaxis ◽  
Emerging Viruses ◽  
Live Virus ◽  
Glycoprotein Antigen ◽  
Ebov Infection ◽  
Exposure Prophylaxis

Abstract Backrgound Convalescent plasma has been used to treat many viral diseases including Ebola. The manufacture of a purified anti-Ebola virus (EBOV) intravenous immunoglobulin (IVIG) from pooled convalescent plasma is described in this paper. Methods An ELISA targeting an EBOV surface glycoprotein antigen was used to determine the immunoglobulin titer of pooled plasma and purified anti-EBOV IVIG. Anti-EBOV IVIG was also tested in neutralization assays using a vesicular stomatitis virus pseudovirion expressing EBOV glycoprotein on its surface and with live EBOV. Finally, the efficacy of the anti-EBOV IVIG was assessed in a mouse model of EBOV infection. Results In the ELISA, the anti-EBOV IVIG was shown to have a seven-fold increase in IgG titer over pooled convalescent plasma. In both the pseudovirion and live virus assays, the anti-EBOV IVIG showed approximately five- to six-fold increased potency over pooled plasma. Anti-EBOV IVIG also significantly improved survivability in mice infected with the virus when administered concurrently or two days after infection. Conclusions These data support this purified anti-EBOV IVIG merits additional investigation and clinical trials for treatment and post-exposure prophylaxis of Ebola virus disease. The experience gained can be applied to manufacture hyperimmune globulins against other emerging viruses.

scholarly journals Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014–2016 Outbreak in West Africa

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 373 ◽  
Author(s):  
Francesca Colavita ◽  
Mirella Biava ◽  
Concetta Castilletti ◽  
Simone Lanini ◽  
Rossella Miccio ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Sierra Leone ◽  
Ebola Virus ◽  
Virus Disease ◽  
Late Phase ◽  
Treatment Center ◽  
Humoral Immune ◽  
Western Africa ◽  
Ebov Infection

Ebola virus (EBOV) infection is characterized by an excessive inflammatory response, a loss of lymphocytes and a general paralysis of the immune system, however pathophysiological mechanisms are not fully understood. In a cohort of 23 fatal and 21 survivors of ebola virus disease (EVD) cases admitted to the Emergency Ebola-Treatment-Center in Goderich (Freetown, Sierra Leone) during the 2014 to 2016 EBOV epidemic in Western Africa, we analyzed the pathway-focused gene expression profile of secreted proteins involved in the immune response and the levels of specific anti-EBOV IgM and IgG from the time of admission till discharge or death. We observed a dysregulated inflammatory response in fatal patients as compared to survivors, mainly consisting of the upregulation of inflammatory mediators, whose extent directly correlated with viremia levels. The upregulation persisted and intensified during the late phase of infection. Relevant differences were also found in humoral immunity, as an earlier and more robust EBOV antibody response was observed in survivor patients.

Understanding the Predictors that Contribute to Liberian Health Care Workers Feeling Protected From Ebola While at Work

2020 ◽  
pp. 1-6
Author(s):  
Kayla Enriquez ◽  
Kanagasabai Udhayashankar ◽  
Michelle Niescierenko
Keyword(s):  
Health Care ◽  
Health Care Workers ◽  
Ebola Virus ◽  
Virus Disease ◽  
Infection Prevention And Control ◽  
Care Workers ◽  
Before And After ◽  
Returning To Work ◽  
Care Worker ◽  
And Control

ABSTRACT Objective: To assess Liberian health care workers’ feelings around safety in returning to work in the setting of the Ebola virus disease outbreak of 2014–2015 after receiving infection prevention and control (IPC) training. Methods: Academic Consortium Combating Ebola in Liberia (ACCEL) training surveys were done at 21 public, Liberian hospitals to understand health care workers’ attitudes surrounding Ebola and whether they felt safe while at work based on multiple factors. Logistic regression was used for analysis. Results: We found that health care workers feeling safe at work during the Ebola outbreak was primarily predicted by the number of IPC/Ebola trainings received pre-ACCEL interventions. Health care workers felt increasingly safer and motivated to return to work as trainings approached 3 (OR 8, p-value < 0.001); however, more than 3 trainings resulted in decreased safety and motivation. In addition, health care workers who reported washing their hands before and after patient contact were 3.4 times more likely to understand how to protect themselves from Ebola. Conclusions: These results help to better understand the utility of repeated trainings on health care worker practice attitudes and the importance of IPC policies within hospitals, such as hand hygiene promotion and education, when coordinating humanitarian efforts.

scholarly journals Evaluation of Ebola Virus Inactivation Procedures for Plasmodium falciparum Malaria Diagnostics: TABLE 1

2015 ◽  
Vol 53 (4) ◽  
pp. 1387-1390 ◽  
Author(s):  
Rachel Lau ◽  
Amanda Wang ◽  
Ann Chong-Kit ◽  
Filip Ralevski ◽  
Andrea K. Boggild
Keyword(s):  
Plasmodium Falciparum ◽  
Differential Diagnosis ◽  
Real Time Pcr ◽  
Ebola Virus ◽  
Virus Disease ◽  
Plasmodium Falciparum Malaria ◽  
Virus Inactivation ◽  
Content Type ◽  
Before And After ◽  
Triton X

Plasmodium falciparummalaria is highly endemic in the three most affected countries in the current epidemic of Ebola virus disease (EVD) in West Africa. As EVD and malaria are clinically indistinguishable, both remain part of the differential diagnosis of ill travelers from returning from areas of EVD transmission. We compared the performances of a rapid diagnostic test (BinaxNOW) and real-time PCR withP. falciparum-positive specimens before and after heat and Triton X-100 inactivation, and we documented no loss of sensitivity.

scholarly journals Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches

2020 ◽  
Author(s):  
Micah T McClain ◽  
Florica J Constantine ◽  
Ricardo Henao ◽  
Yiling Liu ◽  
Ephraim L Tsalik ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Host Response ◽  
Bacterial Pneumonia ◽  
Cell Activation ◽  
B Cell Activation ◽  
Transcriptional Responses ◽  
Transcriptomic Response ◽  
Blood Samples ◽  
Diagnostic Approaches ◽  
Interferon Responses

In order to elucidate novel aspects of the host response to SARS-CoV-2 we performed RNA sequencing on peripheral blood samples across 77 timepoints from 46 subjects with COVID-19 and compared them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a conserved transcriptomic response in peripheral blood that is heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, that persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95). The transcriptome in peripheral blood reveals unique aspects of the immune response in COVID-19 and provides for novel biomarker-based approaches to diagnosis.

scholarly journals Transcriptional analysis of lymphoid tissues from infected nonhuman primates reveals the basis for attenuation and immunogenicity of an Ebola virus encoding a mutant VP35 protein

2021 ◽  
Author(s):  
Amanda Pinski ◽  
Courtney Woolsey ◽  
Allen Jankeel ◽  
Robert Cross ◽  
Christopher F. Basler ◽  
...  
Keyword(s):  
Immune Response ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Transcriptional Response ◽  
Transcriptional Analysis ◽  
Lymphoid Tissues ◽  
High Dose ◽  
Type I ◽  
Wild Type ◽  
Transcriptional Responses

Infection with Zaire ebolavirus (EBOV), a member of the Filoviridae family, causes a disease characterized by high levels of viremia, aberrant inflammation, coagulopathy, and lymphopenia. EBOV initially replicates in lymphoid tissues and disseminates via dendritic cells (DCs) and monocytes to liver, spleen, adrenal gland and other secondary organs. EBOV protein VP35 is a critical immune evasion factor that inhibits type I interferon signaling and DC maturation. Nonhuman primates immunized with a high dose (5x105 PFU) of recombinant EBOV containing a mutated VP35 (VP35m) are protected from challenge with wild-type (wt)EBOV. This protection is accompanied by a transcriptional response in the peripheral blood reflecting a regulated innate immune response and a robust induction of adaptive immune genes. However, the host transcriptional response to VP35m in lymphoid tissues has not been evaluated. Therefore, we conducted a transcriptional analysis of axillary and inguinal lymph nodes, and spleen tissues of NHPs infected with a low dose (2x104 PFU) of VP35m and then backchallenged with a lethal dose of wtEBOV. VP35m induced early transcriptional responses in lymphoid tissues that are distinct from those observed in wtEBOV challenge. Specifically, we detected robust antiviral innate and adaptive responses and fewer transcriptional changes in genes with roles in angiogenesis, apoptosis and inflammation. Two of three macaques survived wtEBOV backchallenge, with only the nonsurvivor displaying a transcriptional response reflecting Ebola virus disease. These data suggest that VP35 is a key modulator of early host responses in lymphoid tissues, thereby regulating disease progression and severity following EBOV challenge. IMPORTANCE Zaire Ebola virus (EBOV) infection causes a severe and often fatal disease characterized by inflammation, coagulation defects, and organ failure driven by a defective host immune response. Lymphoid tissues are key sites of EBOV pathogenesis and generation of an effective immune response to infection. A recent study demonstrated that infection with an EBOV encoding a mutant VP35, a viral protein that antagonizes host immunity, can protect nonhuman primates (NHPs) against lethal EBOV challenge. However, no studies have examined the response to this mutant EBOV in lymphoid tissues. Here, we characterize the gene expression of lymphoid tissues from NHPs challenged with the mutant EBOV and subsequently with wild-type EBOV to identify signatures of a protective host response. Our findings are critical for elucidating viral pathogenesis, mechanisms of host antagonism and the role of lymphoid organs in protective responses to EBOV to improve the development of antivirals and vaccines against EBOV.

scholarly journals Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

2017 ◽  
Vol 9 (385) ◽  
pp. eaai9321 ◽  
Author(s):  
John C. Kash ◽  
Kathie-Anne Walters ◽  
Jason Kindrachuk ◽  
David Baxter ◽  
Kelsey Scherler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Ebola Virus ◽  
Medical Condition ◽  
Virus Disease ◽  
Ebola Virus Disease ◽  
Transcriptional Analysis ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
Course Of Illness

The 2013–2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration–approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance.

scholarly journals Antiviral Innate Responses Induced by VSV-EBOV Vaccination Contribute to Rapid Protection

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Andrea R. Menicucci ◽  
Allen Jankeel ◽  
Heinz Feldmann ◽  
Andrea Marzi ◽  
Ilhem Messaoudi
Keyword(s):  
Gene Expression ◽  
Vesicular Stomatitis Virus ◽  
Cell Activation ◽  
Ebola Virus ◽  
Virus Disease ◽  
Multiorgan Failure ◽  
Ebola Virus Disease ◽  
Phase Iii ◽  
Lethal Challenge ◽  
Vesicular Stomatitis

ABSTRACTEbola virus (EBOV) is a single-stranded RNA virus that causes Ebola virus disease (EVD), characterized by excessive inflammation, lymphocyte apoptosis, hemorrhage, and coagulation defects leading to multiorgan failure and shock. Recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (VSV-EBOV), which is highly efficacious against lethal challenge in nonhuman primates, is the only vaccine that successfully completed a phase III clinical trial. Additional studies showed VSV-EBOV provides complete and partial protection to macaques immunized 7 and 3 days before EBOV challenge, respectively. However, the mechanisms by which this live-attenuated vaccine elicits rapid protection are only partially understood. To address this, we carried out a longitudinal transcriptome analysis of host responses in whole-blood samples collected from cynomolgus macaques vaccinated with VSV-EBOV 28, 21, 14, 7, and 3 days before EBOV challenge. Our findings indicate the transcriptional response to the vaccine peaks 7 days following vaccination and contains signatures of both innate antiviral immunity as well as B-cell activation. EBOV challenge 1 week after vaccination resulted in large gene expression changes suggestive of a recall adaptive immune response 14 days postchallenge. Lastly, the timing and magnitude of innate immunity and interferon-stimulated gene expression correlated with viral burden and disease outcome in animals vaccinated 3 days before challenge.IMPORTANCEEbola virus (EBOV) is the causative agent of Ebola virus disease (EVD), a deadly disease and major public health threat worldwide. A safe and highly efficacious vesicular stomatitis virus-based vaccine against EBOV is the only platform that has successfully completed phase III clinical trials and has been used in recent and ongoing outbreaks. Earlier studies showed that antibodies are the main mode of protection when this vaccine is administered 28 days before EBOV challenge. Recently, we showed this vaccine can provide protection when administered as early as 3 days before challenge and before antibodies are detected. This study seeks to identify the mechanisms of rapid protection, which in turn will pave the way for improved vaccines and therapeutics. Additionally, this study provides insight into host gene expression signatures that could provide early biomarkers to identify infected individuals who are at highest risk of poor outcomes.

scholarly journals Survivors of Ebola Virus Disease Develop Polyfunctional Antibody Responses

2019 ◽  
Vol 221 (1) ◽  
pp. 156-161 ◽  
Author(s):  
Bronwyn M Gunn ◽  
Vicky Roy ◽  
Marcus M Karim ◽  
Jessica N Hartnett ◽  
Todd J Suscovich ◽  
...  
Keyword(s):  
Sierra Leone ◽  
Ebola Virus ◽  
Virus Disease ◽  
Innate Immune ◽  
Ebola Virus Disease ◽  
Immune Effector ◽  
Effector Functions ◽  
Ebov Infection ◽  
Innate Immune Effector ◽  
Functional Antibodies

Abstract Monoclonal antibodies can mediate protection against Ebola virus (EBOV) infection through direct neutralization as well as through the recruitment of innate immune effector functions. However, the antibody functional response following survival of acute EBOV disease has not been well characterized. In this study, serum antibodies from Ebola virus disease (EVD) survivors from Sierra Leone were profiled to capture variation in overall subclass/isotype abundance, neutralizing activity, and innate immune effector functions. Antibodies from EVD survivors exhibited robust innate immune effector functions, mediated primarily by IgG1 and IgA1. In conclusion, development of functional antibodies follows survival of acute EVD.

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