Immunopathology of highly virulent pathogens: insights from Ebola virus

Zampieri, Carisa A.; Sullivan, Nancy J.; Nabel, Gary J.

doi:10.1038/ni1519

Cited by 122 publications

(119 citation statements)

References 63 publications

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“…Ebola viral protein 35 (VP35) is multifunctional, serving as a component of the viral RNA polymerase complex, as a structural/assembly factor, and as a suppressor of host IFN responses (2). Therefore, a functional VP35 is required for efficient viral replication and pathogenesis; knockdown of VP35 leads to reduced viral amplification and reduced lethality in infected mice (14)(15)(16)(17)(18).…”

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“…acterized by fever, shock, coagulation defects, and impaired immunity (1,2). These manifestations of infection are thought to reflect subversion of the innate immune system coupled with uncontrolled viral replication, particularly in macrophages and dendritic cells (3,4).…”

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confidence: 99%

“…Activated IFN genes operate in both autocrine and paracrine manners to stimulate the activity of additional antiviral genes. Therefore, inhibition of signaling mechanisms that promote IFN responses is a necessary viral countermeasure against the host antiviral system and critical for viral propagation (2).…”

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Structure of the Ebola VP35 interferon inhibitory domain

Leung

Ginder

Fulton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

145

195

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Ebola viruses (EBOVs) cause rare but highly fatal outbreaks of viral hemorrhagic fever in humans, and approved treatments for these infections are currently lacking. The Ebola VP35 protein is multifunctional, acting as a component of the viral RNA polymerase complex, a viral assembly factor, and an inhibitor of host interferon (IFN) production. Mutation of select basic residues within the C-terminal half of VP35 abrogates its dsRNA-binding activity, impairs VP35-mediated IFN antagonism, and attenuates EBOV growth in vitro and in vivo. Because VP35 contributes to viral escape from host innate immunity and is required for EBOV virulence, understanding the structural basis for VP35 dsRNA binding, which correlates with suppression of IFN activity, is of high importance. Here, we report the structure of the C-terminal VP35 IFN inhibitory domain (IID) solved to a resolution of 1.4 Å and show that VP35 IID forms a unique fold. In the structure, we identify 2 basic residue clusters, one of which is important for dsRNA binding. The dsRNA binding cluster is centered on Arg-312, a highly conserved residue required for IFN inhibition. Mutation of residues within this cluster significantly changes the surface electrostatic potential and diminishes dsRNA binding activity. The high-resolution structure and the identification of the conserved dsRNA binding residue cluster provide opportunities for antiviral therapeutic design. Our results suggest a structure-based model for dsRNA-mediated innate immune antagonism by Ebola VP35 and other similarly constructed viral antagonists.crystal structure ͉ Ebola virus ͉ RNA binding E bola viruses (EBOVs) cause severe hemorrhagic fever characterized by fever, shock, coagulation defects, and impaired immunity (1, 2). These manifestations of infection are thought to reflect subversion of the innate immune system coupled with uncontrolled viral replication, particularly in macrophages and dendritic cells (3,4). EBOV infection of these cells enhances production of proinflammatory cytokines, such as TNF-␣ and IFN (IFN)-␥, and diminishes stimulation of T cell maturation by dendritic cells (3, 4). Like other negative-strand RNA viruses that impair both innate and adaptive immunity (e.g., influenza, rabies, and measles), EBOV suppresses host IFN activities to replicate, thus resulting in serious disease (5, 6). Only individuals who survive EBOV infection show appreciable amounts of viral-specific antibodies (7), suggesting that EBOV infections lead to shutdown of early immune responses and prevent activation of adaptive immune responses.Recognition of viral particles and viral RNA, including RNA modifications such as 5Ј-triphosphate (5Ј-ppp), by cytosolic pattern recognition receptor helicases RIG-I and MDA-5 leads to activation of transcription factors, including IFN regulatory factor-3 (IRF-3), IRF-7, NF-B, and AP-1 (8-12). These transcription factors in turn induce expression of a large number of cytokines, such as IFN-␣ and IFN-␤ (13). Activated IFN genes operate in both autocrine and paracrin...

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Structure of the Ebola VP35 interferon inhibitory domain

Leung

Ginder

Fulton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

145

195

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“…Notamment, il semble que dans l'épidémie actuelle en Afrique de l'Ouest, ceux-ci soient moins fréquents qu'à l'accoutumé [6]. Dans les infections fatales, le décès est lié de façon générale à une incapacité de la réponse immunitaire à contrôler la croissance virale, ce qui induit une défaillance multiviscérale, une dérégulation du système cardiovas- SYNTHÈSE REVUES [22][23][24][25]. Des nécroses similaires, avec dépôt de fibrine, ont également été décrites dans la pulpe blanche et la pulpe rouge de la rate, modifiant souvent l'architecture de cet organe.…”

Section: Manifestations Cliniques De L'infection à Filovirusunclassified

Dérégulation de l’hémostase dans les infections à filovirus

2015

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Les filovirus ont en commun la structure de leur génome. Celle-ci est composée d'une succession linéaire de gènes, séparée par de courtes régions intergéniques et codant pour la nucléoprotéine NP, la protéine VP35, la protéine VP40, la glycoprotéine sécrétée sGP et la glycoprotéine de surface (GP), la protéine VP30, la protéine VP24 et la polymé-rase L [2,3]. Les protéines NP, VP35, VP30 et L constituent, avec l'ARN viral, le complexe réplicatif permettant la synthèse des ARN messagers viraux et la production d'ARN génomique et anti-génomique viral. Ce complexe, appelé ribonucléoprotéine, est transporté à la membrane plasmique. L'interaction avec la protéine de matrice VP40 déclenche le bourgeonnement des virions à la surface cellulaire. Ceux-ci sont ainsi enveloppés d'une bicouche lipidique et arborent à leur surface la glycoprotéine GP, responsable de l'attachement aux cellules cibles. Cette GP provient de l'édition du gène codant pour la sGP, un phéno-mène exclusivement retrouvé dans les virus Ebola et absent des virus Marburg [3]. Fait intéressant, bien que les protéines des virus Ebola et Marburg soient très similaires, leurs fonctions diffèrent. Ainsi, chez Ebola, la protéine VP24 bloque la réponse à l'interféron, alors que cette fonction est portée par la protéine de matrice VP40 dans le virus Marburg [4,5]. La protéine VP24 du virus Marburg a, quant à elle, été récemment identifiée comme un effecteur important dans la régulation du stress oxydatif, par sa liaison à Keap1 (kelch-like ECHassociated protein 1) [6]. Depuis la découverte du premier filovirus (Marburg 1967), de nombreuses campagnes de recherche ont été entreprises afin de caractériser le réservoir de ces virus. Ces études ont permis d'identifier divers mammifères infectés par le virus Ebola et notamment des CIRI (centre international de recherche en infectiologie), Inserm U1111, laboratoire bases moléculaires de la pathogénicité virale,

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“…However, the complete mechanism leading to changes in vascular endothelial cell permeability have not been elucidated. Several factors, including the release of inflammatory mediators, virus directed attacking of endothelium, the release of endosomal cathepsins and the expression of virus-envelope glycoprotein GP, are proposed to be responsible for virus-induced cell injury and the vascular permeability [1]. GP is considered as a viral determinant of EBOV pathogenicity and likely contributes to hemorrhage during infection, as several groups reported that overexpression of GP can induce cell detachment and rounding in vitro and ex vivo [2].…”

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confidence: 99%