The pathology of experimental Ebola virus infection in monkeys

Baskerville, A.; Bowen, E. T. W.; Platt, G.S.; McArdell, L.B.; Simpson, David

doi:10.1002/path.1711250303

Cited by 114 publications

(85 citation statements)

References 10 publications

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“…Results from many studies have shown biochemical and histological evidence of disseminated intravascular coagulation in both experimentally infected NHPs and humans 19,20,22,23,40,[44][45][46][49][50][51]53,54,70,[73][74][75][76][77][78][79] . The mechanisms that cause these coagulation disorders are not fully understood, but the expression or release of tissue factor from filovirus-infected monocytes and macro phages seems to play a role 54,55 .…”

Section: Type I Transmembrane Proteinmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Type I Transmembrane Proteinmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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“…The coagulation picture is clearer for nonhuman primates. Numerous studies showed histological and biochemical evidence of DIC syndromes in EBOV infection of a variety of nonhuman primate species [32,33,[38][39][40][41][42][43][44][45][46][47].…”

Section: Animal Models Of Ebola Hfmentioning

confidence: 99%

Towards a Vaccine Against Ebola Virus

Geisbert¹,

Jahrling²

2003

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Ebola virus infection causes hemorrhagic fever with high mortality rates in humans and nonhuman primates. Currently, there are no vaccines or therapies approved for human use. Outbreaks of Ebola virus have been infrequent, largely confined to remote locations in Africa and quarantine of sick patients has been effective in controlling epidemics. In the past, this small global market has generated little commercial interest for developing an Ebola virus vaccine. However, heightened awareness of bioterrorism advanced by the events surrounding September 11, 2001, concomitant with knowledge that the former Soviet Union was evaluating Ebola virus as a weapon, has dramatically changed perspectives regarding the need for a vaccine against Ebola virus. This review takes a brief historic look at attempts to develop an efficacious vaccine, provides an overview of current vaccine candidates and highlights strategies that have the greatest potential for commercial development. Ebola virus (EBOV) has gained public notoriety in the last decade largely as a result of the enormous interest and alarm generated by the news media. This attention is primarily a consequence of the highly publicized isolation of EBOV in a suburb of Washington, DC., in 1989 coupled with its high case-fatality rate (near 90% in some outbreaks), unusual and striking morphology and its dramatic clinical presentation and lack of effective specific treatment. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating have been slow, primarily because these viruses require biosafety level (BSL)-4 containment for safe research.EBOV infections are usually the most severe of the viruses that cause hemorrhagic fever (HF). Clinical symptoms appear suddenly after an incubation period of 2 to 21 days [1]. Common presenting complaints include high fever, chills, malaise and myalgia [2][3][4][5][6][7]. As the disease progresses, there is evidence of multisystemic involvement and manifestations include prostration, anorexia, vomiting, nausea, abdominal pain, diarrhea, shortness of breath, sore throat, edema, confusion and coma [2][3][4][5][6][7]. Petechiae, ecchymoses, mucosal hemorrhages and uncontrolled bleeding at venipuncture sites are notable observations [2][3][4][5][6][7]. The presence of a maculopapular rash is a prominent feature [2][3][4][5][6][7] but is not pathognomonic for EBOV HF. Fulminant EBOV infection typically evolves to shock, convulsions and, in most cases, diffuse coagulopathy ensues [2][3][4][5][6][7]. It should be noted that evidence of asymptomatic Ebola infection was documented in a small group of individuals during a recent outbreak [8] but the clinical and epidemiological relevance of this observation, at this time, is uncertain. Genetics & viral proteinsThe family Filoviridae is comprised of two genera: Marburgvirus (MARV) and Ebolavirus (EBOV). The Ebolavirus genus is further subdivided into four distinct species: Ivory Coast ebolavirus (ICEBOV), Reston Ebolavirus (REBOV), Su...

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“…EBOV replicates to high titers in the liver (12)(13)(14), and fatal infection is associated with alterations in circulating enzyme levels indicative of liver damage (15)(16)(17). Microscopic analysis of infected livers shows histopathologic lesions, including hepatocyte damage and death (14,18,19). However, previous studies have not described apoptosis as a mechanism of cell death in hepatocytes during EBOV infection.…”

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confidence: 99%

Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

Bradfute

Swanson

Smith

et al. 2009

The Journal of Immunology

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Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever, resulting in death in up to 90% of infected humans. EBOV infection induces massive bystander lymphocyte apoptosis; however, neither the cellular apoptotic pathway(s) nor the systemic implications of lymphocyte apoptosis in EBOV infection are known. In this study, we show data suggesting that EBOV-induced lymphocyte apoptosis in vivo occurs via both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways, as both Fas-associated death domain dominant negative transgenic mice and mice overexpressing bcl-2 were resistant to EBOV-induced lymphocyte apoptosis. Surprisingly, inhibiting lymphocyte apoptosis during EBOV infection did not result in improved animal survival. Furthermore, we show for the first time that hepatocyte apoptosis likely occurs in EBOV infection, and that mice lacking the proapoptotic genes Bim and Bid had reduced hepatocyte apoptosis and liver enzyme levels postinfection. Collectively, these data suggest that EBOV induces multiple proapoptotic stimuli and that blocking lymphocyte apoptosis is not sufficient to improve survival in EBOV infection. These data suggest that hepatocyte apoptosis may play a role in the pathogenesis of EBOV infection, whereas lymphocyte apoptosis appears to be nonessential for EBOV disease progression.

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The pathology of experimental Ebola virus infection in monkeys

Cited by 114 publications

References 10 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Towards a Vaccine Against Ebola Virus

Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

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