scholarly journals Antagonism of STAT3 signalling by Ebola virus

2020 ◽  
Author(s):  
Angela R. Harrison ◽  
Megan Dearnley ◽  
Shawn Todd ◽  
Diane Green ◽  
Glenn A. Marsh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ebola Virus ◽  
Significant Risk ◽  
Disease Outbreaks ◽  
Case Fatality ◽  
Cell Physiology ◽  
Haemorrhagic Fever ◽  
Nuclear Trafficking ◽  
Ebov Infection ◽  
Stat3 Signalling

AbstractMany viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon (IFN) signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin (IL-) 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to IL-6 family cytokines, and that this is mediated by the IFN-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.Author summaryEbola virus (EBOV) continues to pose a significant risk to human health globally, causing ongoing disease outbreaks with case-fatality rates between 40 and 60%. Suppression of immune responses is a critical component of EBOV haemorrhagic fever, but understanding of EBOV impact on signalling by cytokines other than interferon is limited. We find that infectious EBOV inhibits interleukin-6 cytokine signalling via antagonism of STAT3. The antagonistic strategy uniquely combines two distinct mechanisms, which appear to reflect differing nuclear trafficking mechanisms of critical STAT3 complexes. This provides fundamental insights into the mechanisms of pathogenesis of a lethal virus, and biology of STAT3, a critical player in immunity, development, growth and cancer.

scholarly journals Antagonism of STAT3 signalling by Ebola virus

2021 ◽  
Vol 17 (6) ◽  
pp. e1009636
Author(s):  
Angela R. Harrison ◽  
Shawn Todd ◽  
Megan Dearnley ◽  
Cassandra T. David ◽  
Diane Green ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Ebola Virus ◽  
Cell Physiology ◽  
Nuclear Trafficking ◽  
Signal Transducers ◽  
Host Interactions ◽  
Ebov Infection ◽  
Interferon Signalling ◽  
Stat3 Signalling

Many viruses target signal transducers and activators of transcription (STAT) 1 and 2 to antagonise antiviral interferon signalling, but targeting of signalling by other STATs/cytokines, including STAT3/interleukin 6 that regulate processes important to Ebola virus (EBOV) haemorrhagic fever, is poorly defined. We report that EBOV potently inhibits STAT3 responses to interleukin-6 family cytokines, and that this is mediated by the interferon-antagonist VP24. Mechanistic analysis indicates that VP24 effects a unique strategy combining distinct karyopherin-dependent and karyopherin-independent mechanisms to antagonise STAT3-STAT1 heterodimers and STAT3 homodimers, respectively. This appears to reflect distinct mechanisms of nuclear trafficking of the STAT3 complexes, revealed for the first time by our analysis of VP24 function. These findings are consistent with major roles for global inhibition of STAT3 signalling in EBOV infection, and provide new insights into the molecular mechanisms of STAT3 nuclear trafficking, significant to pathogen-host interactions, cell physiology and pathologies such as cancer.

scholarly journals The Ebola outbreak, 2013–2016: old lessons for new epidemics

2017 ◽  
Vol 372 (1721) ◽  
pp. 20160297 ◽  
Author(s):  
Cordelia E. M. Coltart ◽  
Benjamin Lindsey ◽  
Isaac Ghinai ◽  
Anne M. Johnson ◽  
David L. Heymann
Keyword(s):  
Decision Making ◽  
West Africa ◽  
Disease Control ◽  
Ebola Virus ◽  
Case Fatality ◽  
West African ◽  
Lessons Learned ◽  
Haemorrhagic Fever ◽  
Chronological Order ◽  
Epidemiological Parameters

Ebola virus causes a severe haemorrhagic fever in humans with high case fatality and significant epidemic potential. The 2013–2016 outbreak in West Africa was unprecedented in scale, being larger than all previous outbreaks combined, with 28 646 reported cases and 11 323 reported deaths. It was also unique in its geographical distribution and multicountry spread. It is vital that the lessons learned from the world's largest Ebola outbreak are not lost. This article aims to provide a detailed description of the evolution of the outbreak. We contextualize this outbreak in relation to previous Ebola outbreaks and outline the theories regarding its origins and emergence. The outbreak is described by country, in chronological order, including epidemiological parameters and implementation of outbreak containment strategies. We then summarize the factors that led to rapid and extensive propagation, as well as highlight the key successes, failures and lessons learned from this outbreak and the response. This article is part of the themed issue ‘The 2013–2016 West African Ebola epidemic: data, decision-making and disease control’.

scholarly journals Maternal and Infant Death and the rVSV-ZEBOV Vaccine Through Three Recent Ebola Virus Epidemics-West Africa, DRC Équateur and DRC Kivu: 4 Years of Excluding Pregnant and Lactating Women and Their Infants from Immunization

2019 ◽  
Vol 6 (4) ◽  
pp. 213-222 ◽  
Author(s):  
David A. Schwartz
Keyword(s):  
At Risk ◽  
Clinical Trials ◽  
West Africa ◽  
Pregnant Women ◽  
Ebola Virus ◽  
Disease Outbreaks ◽  
Case Fatality ◽  
Viral Disease ◽  
Lactating Women ◽  
Health Communities

Abstract Purpose of Review Ebola virus infection has one of the highest overall case fatality rates of any viral disease. It has historically had an especially high case mortality rate among pregnant women and infants—greater than 90% for pregnant women in some outbreaks and close to 100 % in fetuses and newborns. The Merck recombinant vaccine against Ebola virus, termed rVSV-ZEBOV, underwent clinical trials during the 2013–2015 West Africa Ebola epidemic where it was found to be 100% efficacious. It was subsequently used during the 2018 DRC Équateur outbreak and in the 2018 DRC Kivu Ebola which is still ongoing, where its efficacy is 97.5 %. Pregnant and lactating women and their infants have previously been excluded from the design, clinical trials, and administration of many vaccines and drugs. This article critically examines the development of the rVSV-ZEBOV vaccine and its accessibility to pregnant and lactating women and infants as a life-saving form of prevention through three recent African Ebola epidemics—West Africa, DRC Équateur, and DRC Kivu. Recent Findings Pregnant and lactating women and their infants were excluded from participation in the clinical trials of rVSV-ZEBOV conducted during the West Africa epidemic. This policy of exclusion was continued with the occurrence of the DRC Équateur outbreak in 2018, in spite of calls from the public health and global maternal health communities to vaccinate this population. Following the onset of the DRC Kivu epidemic, the exclusion persisted. Eventually, the policy was reversed to include vaccination of pregnant and lactating women. However, it was not implemented until June 2019, 10 months after the start of the epidemic, placing hundreds of women and infants at risk for this highly fatal infection. Summary The historical policy of excluding pregnant and lactating women and infants from vaccine design, clinical trials, and implementation places them at risk, especially in situations of infectious disease outbreaks. In the future, all pregnant women, regardless of trimester, breastfeeding mothers, and infants, should have access to the Ebola vaccine.

The Epidemiological Presentation Pattern of Ebola Virus Disease Outbreaks: Changes from 1976 to 2019

2020 ◽  
Vol 35 (3) ◽  
pp. 247-253
Author(s):  
Pedro Arcos González ◽  
Ángel Fernández Camporro ◽  
Anneli Eriksson ◽  
Carmen Alonso Llada
Keyword(s):  
At Risk ◽  
Ebola Virus ◽  
Virus Disease ◽  
Disease Outbreaks ◽  
Case Fatality ◽  
Ebola Virus Disease ◽  
World Health ◽  
Study Objective ◽  
Population At Risk ◽  
Case Fatality Ratio

AbstractIntroduction:Ebola Virus Disease (EVD) is the international health emergency paradigm due to its epidemiological presentation pattern, impact on public health, resources necessary for its control, and need for a national and international response.Study Objective:The objective of this work is to study the evolution and progression of the epidemiological presentation profile of Ebola disease outbreaks since its discovery in 1976 to the present, and to explore the possible reasons for this evolution from different perspectives.Methods:Retrospective observational study of 38 outbreaks of Ebola disease occurred from 1976 through 2019, excluding laboratory accidents. United Nations agencies and programs; Ministries of Health; the US Centers for Disease Control and Prevention (CDC); ReliefWeb; emergency nongovernmental organizations; and publications indexed in PubMed, EmBase, and Clinical Key have been used as sources of data. Information on the year of the outbreak, date of beginning and end, duration of the outbreak in days, number of cases, number of deaths, population at risk, geographic extension affected in Km2, and time of notification of the first cases to the World Health Organization (WHO) have been searched and analyzed.Results:Populations at risk have increased (P = .024) and the geographical extent of Ebola outbreaks has grown (P = .004). Reporting time of the first cases of Ebola to WHO has been reduced (P = .017) and case fatality (P = .028) has gone from 88% to 62% in the period studied. There have been differences (P = .04) between the outbreaks produced by the Sudan and Zaire strains of the virus, both in terms of duration and case fatality ratio (Sudan strain 74.5 days on average and 62.7% of case fatality ratio versus Zaire strain with 150 days on average and 55.4% case fatality ratio).Conclusion:There has been a change in the epidemiological profile of the Ebola outbreaks from 1976 through 2019 with an increase in the geographical extent of the outbreaks and the population at risk, as well as a significant decrease in the outbreaks case fatality rate. There have been advances in the detection and management capacity of outbreaks, and the notification time to the WHO has been reduced. However, there are social, economic, cultural, and political obstacles that continue to greatly hinder a more efficient epidemiological approach to Ebola disease, mainly in Central Africa.

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

2004 ◽  
Vol 6 (20) ◽  
pp. 1-24 ◽  
Author(s):  
Thomas W. Geisbert ◽  
Lisa E. Hensley
Keyword(s):  
Ebola Virus ◽  
Clinical Presentation ◽  
Case Fatality ◽  
Regulatory Elements ◽  
Current Understanding ◽  
Therapeutic Interventions ◽  
Therapeutic Modality ◽  
Washington Dc ◽  
Lethal Infection ◽  
Ebov Infection

Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicised isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection.

Letter-to-Editor II

2014 ◽  
Vol 6 (2) ◽  
pp. 0-0
Author(s):  
Ayush Agarwal ◽  
Omkar Singh ◽  
VK Rastogi
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Specific Treatment ◽  
Disease Outbreaks ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Physical Contact ◽  
Ebola Virus Disease ◽  
Human Beings ◽  
Ebola Hemorrhagic Fever

ABSTRACT • Ebola virus disease (EVD), also known as Ebola hemorrhagic fever, is a severe, often fatal illness of human beings having a case fatality rate of up to 90%. • Ebola virus disease outbreaks occur primarily in remote Central and West Africa, near the tropical rainforests. • The virus is transmitted to humans from wild animals and spreads in the human beings through physical contact. • It does not transmit through vectors or air-borne droplets. • Severely ill patients require intensive supportive care. No specific treatment or vaccine is available for use.

scholarly journals Tolerance and Persistence of Ebola Virus in Primary Cells from Mops condylurus, a Potential Ebola Virus Reservoir

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2186
Author(s):  
Marcel Bokelmann ◽  
Uwe Vogel ◽  
Franka Debeljak ◽  
Ariane Düx ◽  
Silke Riesle-Sbarbaro ◽  
...  
Keyword(s):  
Potential Role ◽  
Ebola Virus ◽  
Virus Disease ◽  
Disease Outbreaks ◽  
Integral Membrane Protein ◽  
Reservoir Host ◽  
Primary Cells ◽  
Cytopathic Effects ◽  
Ebov Infection

Although there have been documented Ebola virus disease outbreaks for more than 40 years, the natural reservoir host has not been identified. Recent studies provide evidence that the Angolan free-tailed bat (Mops condylurus), an insectivorous microbat, is a possible ebolavirus reservoir. To investigate the potential role of this bat species in the ecology of ebolaviruses, replication, tolerance, and persistence of Ebola virus (EBOV) were investigated in 10 different primary bat cell isolates from M. condylurus. Varying EBOV replication kinetics corresponded to the expression levels of the integral membrane protein NPC1. All primary cells were highly tolerant to EBOV infection without cytopathic effects. The observed persistent EBOV infection for 150 days in lung primary cells, without resultant selective pressure leading to virus mutation, indicate the intrinsic ability of EBOV to persist in this bat species. These results provide further evidence for this bat species to be a likely reservoir of ebolaviruses.

scholarly journals Early Transcriptional Changes within Liver, Adrenal Gland, and Lymphoid Tissues Significantly Contribute to Ebola Virus Pathogenesis in Cynomolgus Macaques

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
Allen Jankeel ◽  
Andrea R. Menicucci ◽  
Courtney Woolsey ◽  
Karla A. Fenton ◽  
Norma Mendoza ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Adrenal Glands ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Organ Damage ◽  
Host Responses ◽  
Lymphoid Tissues ◽  
Cynomolgus Macaques ◽  
Ebov Infection ◽  
Transcriptional Changes

ABSTRACT Ebola virus (EBOV) continues to pose a significant threat to human health, as evidenced by the 2013–2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures makes EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, and angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses in lymphoid tissues were confirmed with flow cytometry. Together, these data suggest that the liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease. IMPORTANCE Ebola virus (EBOV) remains a high-priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands, and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated, while inflammation-related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands, and lymphoid tissues contribute to EBOV pathogenesis.

scholarly journals Single-cell profiling of Ebola virus infection in vivo reveals viral and host transcriptional dynamics

2020 ◽  
Author(s):  
Dylan Kotliar ◽  
Aaron E. Lin ◽  
James Logue ◽  
Travis K. Hughes ◽  
Nadine M. Khoury ◽  
...  
Keyword(s):  
Single Cell ◽  
Ebola Virus ◽  
Immune Cell ◽  
Temporal Dynamics ◽  
Cell Activity ◽  
Case Fatality ◽  
Protein Quantification ◽  
Cell Protein ◽  
Ebov Infection

SummaryEbola virus (EBOV) causes epidemics with high case fatality rates, yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. To better understand EBOV infection in vivo, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cell activity during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, providing insight into pathogenesis. We find that immature, proliferative monocyte-lineage cells with reduced antigen presentation capacity replace conventional circulating monocyte subsets within days of infection, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying viral RNA abundance in individual cells, we identify molecular determinants of tropism and examine temporal dynamics in viral and host gene expression. Within infected cells, we observe that EBOV down-regulates STAT1 mRNA and interferon signaling, and up-regulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating cellular pathways the virus manipulates for its replication. Overall, this study sheds light on EBOV tropism, replication dynamics, and elicited immune response, and provides a framework for characterizing interactions between hosts and emerging viruses in a maximum containment setting.

scholarly journals The Ebola virus interferon antagonist VP24 undergoes active nucleocytoplasmic trafficking

2020 ◽  
Author(s):  
Angela R. Harrison ◽  
Gregory W. Moseley
Keyword(s):  
Viral Replication ◽  
Immune Evasion ◽  
Nuclear Import ◽  
Nuclear Export ◽  
Ebola Virus ◽  
Molecular Mapping ◽  
Case Fatality ◽  
Nucleocytoplasmic Transport ◽  
Nucleocytoplasmic Trafficking ◽  
Nuclear Trafficking

AbstractViral interferon (IFN) antagonist proteins mediate evasion of IFN-mediated innate immunity and are often multifunctional, having distinct roles in viral replication processes. Functions of the Ebola virus (EBOV) IFN antagonist VP24 include nucleocapsid assembly during cytoplasmic replication and inhibition of IFN-activated signalling by STAT1. For the latter, VP24 prevents STAT1 nuclear import via competitive binding to nuclear import receptors (karyopherins). Many viral proteins, including proteins from viruses with cytoplasmic replication cycles, interact with the trafficking machinery to undergo nucleocytoplasmic transport, with key roles in pathogenesis. Despite established karyopherin interaction, the nuclear trafficking profile of VP24 has not been investigated. We find that VP24 becomes strongly nuclear following overexpression of karyopherin or inhibition of nuclear export pathways. Molecular mapping indicates that cytoplasmic localisation of VP24 depends on a CRM1-dependent nuclear export sequence at the VP24 C-terminus. Nuclear export is not required for STAT1 antagonism, consistent with competitive karyopherin binding being the principal antagonistic mechanism while export mediates return of nuclear VP24 to the cytoplasm for replication functions. Thus, nuclear export of VP24 might provide novel targets for antiviral approaches.ImportanceEbola virus (EBOV) is the causative agent of ongoing outbreaks of severe haemorrhagic fever with case-fatality rates between 40 and 60%. Proteins of many viruses with cytoplasmic replication cycles similar to EBOV interact with the nuclear trafficking machinery, resulting in active nucleocytoplasmic shuttling important to immune evasion and other intranuclear functions. However, exploitation of host trafficking machinery for nucleocytoplasmic transport by EBOV has not been directly examined. We find that the EBOV protein VP24 is actively trafficked between the nucleus and cytoplasm, and identify the specific pathways and sequences involved. The data indicate that nucleocytoplasmic trafficking is important for the multifunctional nature of VP24, which has critical roles in immune evasion and viral replication, identifying a new mechanism in infection by this highly lethal pathogen, and potential target for antivirals.

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