Markedly Elevated Levels of Interferon (IFN)‐σ, IFN‐α, Interleukin (IL)‐2, IL‐10, and Tumor Necrosis Factor‐α Associated with Fatal Ebola Virus Infection

Villinger, François; Rollin, Pierre E.; Brar, Sukhdev S.; Chikkala, Nathaniel F.; Winter, Jörn; Sundstrom, J. Bruce; Zaki, Sherif R.; Swanepoel, Robert; Ansari, Aftab A.; Peters, C. J.

doi:10.1086/514283

Cited by 296 publications

(250 citation statements)

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“…Systematic studies in experimentally infected NHPs suggest that monocytes, macrophages and dendritic cells are the early replication sites for EBOV and MARV 41,48,51 . Filovirus infection of mononuclear phagocytes is thought to trigger a series of events that includes the production and release of the procoagulant protein tissue factor 54,55 and an assortment of pro-inflammatory cytokines, chemokines and free radical species in NHPs and humans 48,51,[55][56][57][58][59][60][61][62][63][64][65][66][67][68] . This dysregulated host response likely plays a greater role in the development of the observed pathology than any structural damage caused by viral replication in host cells and/or tissues.…”

Section: Pathology and Tissue Tropismmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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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: Pathology and Tissue Tropismmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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Section: Discussionmentioning

confidence: 99%

“…Other recent studies suggest that cytokines may play an important role in filoviral disease. Elevated cytokine levels were shown in acute sera of patients infected with EBO-Z in former Zaire (Villinger et al, 1999) as well as from filovirus-infected monkeys (Ignat'ev et al, 1996).Apoptosis of lymphocytes in filovirus-infected tissues could be mediated by stimulation with a structural or virus-induced protein. Studies of HIV-infected monocytes suggested that interaction of CD4 with expressed gp120 in conjunction with other cell surface proteins may predispose cells to undergo apoptosis in the absence of viral infection (Coito and Bomsel, 1999).…”

mentioning

confidence: 99%

Apoptosis Induced In Vitro and In Vivo During Infection by Ebola and Marburg Viruses

Geisbert

Hensley

Gibb

et al. 2000

Laboratory Investigation

289

254

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SUMMARY:Induction of apoptosis has been documented during infection with a number of different viruses. In this study, we used transmission electron microscopy (TEM) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling to investigate the effects of Ebola and Marburg viruses on apoptosis of different cell populations during in vitro and in vivo infections. Tissues from 18 filovirus-infected nonhuman primates killed in extremis were evaluated. Apoptotic lymphocytes were seen in all tissues examined. Filoviral replication occurred in cells of the mononuclear phagocyte system and other well-documented cellular targets by TEM and immunohistochemistry, but there was no evidence of replication in lymphocytes. With the exception of intracytoplasmic viral inclusions, filovirus-infected cells were morphologically normal or necrotic, but did not exhibit ultrastructural changes characteristic of apoptosis. In lymph nodes, filoviral antigen was co-localized with apoptotic lymphocytes. Examination of cell populations in lymph nodes showed increased numbers of macrophages and concomitant depletion of CD8 ϩ T cells and plasma cells in filovirus-infected animals. This depletion was particularly striking in animals infected with the Zaire subtype of Ebola virus. In addition, apoptosis was demonstrated in vitro in lymphocytes of filovirus-infected human peripheral blood mononuclear cells by TEM. These findings suggest that lymphopenia and lymphoid depletion associated with filoviral infections result from lymphocyte apoptosis induced by a number of factors that may include release of various chemical mediators from filovirus-infected or activated cells, damage to the fibroblastic reticular cell conduit system, and possibly stimulation by a viral protein. (Lab Invest 2000, 80:171-186).I nfections with filoviruses cause severe and often fatal hemorrhagic disease in humans and nonhuman primates, killing up to 90% of infected individuals. Ebola (EBO) and Marburg (MBG) viruses comprise the family Filoviridae (Murphy et al, 1995). The EBO species consists of the Zaire and Sudan subtypes first isolated during separate outbreaks in 1976, the Reston subtype initially isolated from monkeys imported from the Philippines to the United States in 1989, and the Cô te d'Ivoire subtype discovered in the Tai Forest of the Ivory Coast in 1994. The recent re-emergence of EBO subtype Zaire (EBO-Z) in former Zaire and Gabon, and subtype Reston (EBO-R) in the United States, are but the last of a succession of filoviral outbreaks that have occurred sporadically since the initial zoonotic outbreak of MBG in 1967. Although outbreaks have been self-limiting, the lack of proven effective prophylactic or therapeutic regimens to treat filoviral infections has heightened concerns about the public health threat of these pathogens.The factors contributing to the development of severe lesions in EBO and MBG hemorrhagic fevers are unknown. Filoviral infections of humans and nonhuman primates are characterized by a failure o...

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“…Ebola virus infections frequently result in severe hemorrhagic fever, and epidemics of the Ebola virus, Zaire subtype have resulted in mortality rates of greater than 80% (1,2). The pathologic features and the immune responses characteristic of fatal and nonfatal human Ebola virus infections have begun to be characterized (3)(4)(5). Additionally, the mechanisms by which Ebola viruses induce hemorrhage and shock are beginning to be explored.…”

mentioning

confidence: 99%