Human Fatal Zaire Ebola Virus Infection Is Associated with an Aberrant Innate Immunity and with Massive Lymphocyte Apoptosis

Wauquier, Nadia; Becquart, Pierre; Padilla, Cindy; Baize, Sylvain; Leroy, Eric M.

doi:10.1371/journal.pntd.0000837

Cited by 330 publications

(392 citation statements)

References 65 publications

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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

106

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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

106

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“…In the second case, a lumbar puncture was performed at day 41 after EVD onset; Ebola virus was detected at a cycle threshold (CT) value of 37.6, but further CSF analysis was not available [24]. Although not typical laboratory analyses, cytokine analyses on patients with Ebola have in the past revealed a Bcytokine storm^, with increased proinflammatory cytokine and chemokine production in patients with Ebola, particularly in those with more severe disease [28]. …”

Section: Laboratory Findingsmentioning

confidence: 99%

Neurological Complications of Ebola Virus Infection

2016

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Ebola virus disease is one of the deadliest pathogens known to man, with a mortality rate between 25-90% depending on the species and outbreak of Ebola. Typically, it presents with fever, headache, voluminous vomiting and diarrhea, and can progress to a hemorrhagic illness; neurologic symptoms, including meningoencephalitis, seizures, and coma, can also occur. Recently, an outbreak occurred in West Africa, affecting > 28,000 people, and killing > 11,000. Owing to the magnitude of this outbreak, and the large number (>17,000) of Ebola survivors, the medical and scientific communities are learning much more about the acute manifestations and sequelae of Ebola. A number of neurologic complications can occur after Ebola, such as seizures, memory loss, headaches, cranial nerve abnormalities, and tremor. Ebola may also persist in some immunologically privileged sites, including the central nervous system, and can rarely lead to relapse in disease. Owing to these findings, it is important that survivors are evaluated and monitored for neurologic symptoms. Much is unknown about this disease, and treatment remains largely supportive; however, with ongoing clinical and basic science, the mechanisms of how Ebola affects the central nervous system and how it persists after acute disease will hopefully become more clear, and better treatments and clinical practices for Ebola patients will be developed.

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Section: Introductionmentioning

confidence: 99%

“…Moreover, restoration of naïve T-cell numbers after acute T-cell depletion, whether caused by infection, chemotherapy, or bone marrow transplantation requires cell division. Both naïve T-cell division and cell survival are dependent on extrinsic cues provided by IL-7 and tonic trophic signals obtained via the T-cell receptor (TCR) through interaction with specific self-pMHC [2][3][4][5][6][7].It is well-established that T-cell division during antigen-specific responses is a function of the number of the antigen-specific T cells present, such that large numbers of T cells with the same TCR inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance.…”

mentioning

confidence: 99%

“…Despite the demonstration of competition for pMHC signals both for maintenance and in driving T-cell division, it remains unclear how heterogeneity among T cells in self-reactivity impacts their ability to compete and in what ways such competition influences the TCRs present in the peripheral repertoire. This is important in determining how and why the T-cell repertoire changes with age and after acute T-cell depletion, whether caused by sepsis, viral infections such as HIV or Ebola, or as a result of chemotherapy [5][6][7]. …”

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confidence: 99%

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Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

et al. 2016

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T-cell division is central to maintaining a stable T-cell pool in adults. It also enables T-cell expansion in neonates, and after depletion by chemotherapy, bone marrow transplantation, or infection. The same signals required for T-cell survival in lymphoreplete settings, IL-7 and T-cell receptor (TCR) interactions with self-peptide MHC (pMHC), induce division when T-cell numbers are low. The strength of reactivity for self-pMHC has been shown to correlate with the capacity of T cells to undergo lymphopenia-induced proliferation (LIP),in that weakly self-reactive T cells are unable to divide, implying that T-cell reconstitution would significantly skew the TCR repertoire toward TCRs with greater self-reactivity and thus compromise T-cell diversity. Here, we show that while CD4 + T cells with low self-pMHC reactivity experience more intense competition, they are able to divide when present at low enough cell numbers. Thus, at physiological precursor frequencies CD4 + T cells with low self-pMHC reactivity are able to contribute to the reconstitution of the T-cell pool.Keywords: Lymphopenia-induced proliferation r Regulation of homeostasis r T-cell competition r T-cell diversity r T-cell repertoire Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe size of the naïve T-cell pool is tightly regulated. On average, naïve T cells are long-lived, but both in humans and mice there is continual turnover with cells dying and being replaced. Two sources of renewal contribute to naïve T-cell maintenance: de novo production in the thymus and proliferation within secondary Correspondence: Dr. Nienke Vrisekoop and Dr. Judith Mandl e-mail: n.vrisekoop@umcutrecht.nl; judith.mandl@mcgill.ca lymphoid organs. In adults, when thymic production diminishes, 90% of daily naïve T-cell production derives from proliferation [1]. Moreover, restoration of naïve T-cell numbers after acute T-cell depletion, whether caused by infection, chemotherapy, or bone marrow transplantation requires cell division. Both naïve T-cell division and cell survival are dependent on extrinsic cues provided by IL-7 and tonic trophic signals obtained via the T-cell receptor (TCR) through interaction with specific self-pMHC [2][3][4][5][6][7].It is well-established that T-cell division during antigen-specific responses is a function of the number of the antigen-specific T cells present, such that large numbers of T cells with the same TCR inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance. In lympho-replete mice, T cells have a longer average life span when there are less competitor cells present with the same TCR [10]. Furthermore, during lymphopenia-induced proliferation (LIP), T cells divide in the presence of T cells with a distinct TCR, but not when there are large numbers of T cells present with the same TCR [11][12][13]. This suggests that signals obtained from sub-threshold interactions...

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Human Fatal Zaire Ebola Virus Infection Is Associated with an Aberrant Innate Immunity and with Massive Lymphocyte Apoptosis

Cited by 330 publications

References 65 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Neurological Complications of Ebola Virus Infection

Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

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