Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever

Bray, Mike; Geisbert, Thomas W.

doi:10.1016/j.biocel.2005.02.018

Cited by 240 publications

(189 citation statements)

References 27 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…These include viral glycoprotein-mediated cytotoxicity, dysregulation of the coagulation cascade due to the production of tissue factor, and the production of proinflammatory cytokines (10,16,17,51,54,57). General immunosuppression also appears to be a characteristic of EBOV infection (7,46), and inhibition of dendritic cell and macrophage activation are among the possible mechanisms of this suppression (5,18,38). These processes likely occur as a result of active viral replication.…”

Section: Ebola Virus (Ebov) and Marburg Virus Comprise The Familymentioning

confidence: 99%

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Reid

Valmas

Martinez

et al. 2007

J Virol

224

249

View full text Add to dashboard Cite

The Zaire ebolavirus protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-␣/␤)-and IFN-␥-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-␣/␤-and IFN-␥-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin ␣1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin ␣1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin ␣1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin ␣1. We assessed the binding of both PY-STAT1 and the VP24 proteins from Zaire, mouse-adapted Zaire, and Reston Ebola viruses for interaction with all six members of the human karyopherin ␣ family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin ␣1 but also with karyopherins ␣5 and ␣6, which together comprise the NPI-1 subfamily of karyopherin ␣s. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins ␣1, ␣5, and ␣6. Consistent with their ability to inhibit the karyopherin-PY-STAT1 interaction, Zaire, mouse-adapted Zaire, and Reston Ebola virus VP24s displayed similar capacities to inhibit IFN-␤-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins ␣1, ␣5, or ␣6 by binding within the PY-STAT1 binding region of the karyopherins and that this function is conserved among the VP24 proteins of different Ebola virus species.

show abstract

Section: Ebola Virus (Ebov) and Marburg Virus Comprise The Familymentioning

confidence: 99%

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Reid

Valmas

Martinez

et al. 2007

J Virol

224

249

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

Structure of the Ebola VP35 interferon inhibitory domain

Leung

Ginder

Fulton

et al. 2009

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

145

195

View full text Add to dashboard Cite

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...

show abstract

“…The massive apoptosis of "bystander" NK and T cells further impairs the immune functions (Reed et al, 2004). However, in a study, treatment of infected macaques with a tissue-factor inhibitor reduced both inflammation and viral replication and improved survival (Bray and Geisbert, 2005). Therefore, these findings suggest that modifying host responses would be an effective therapeutic strategy against ebola.…”

Section: Strengths Of Ebola Virusmentioning

confidence: 99%

THE STRENGTHS, WEAKNESSES, OPPORTUNITIES, AND THREATS (SWOTs) ANALYSES OF THE EBOLA VIRUS

Babalola

2016

AJID

View full text Add to dashboard Cite

Background: Owing to the extreme virulence and case fatality rate of ebola virus disease (EVD), there had been so much furore, panic and public health emergency about the possible pandemic from the recent West African outbreak of the disease, with attendant handful research, both in the past and most recently. The magnitude of the epidemic of ebola virus disease has prompted global interest and urgency in the discovery of measures to mitigate the impact of the disease. Researchers in the academia and the industry were pressured to only focus on the development of effective and safe ebola virus vaccines, without consideration of the other aspects to this virus, which may influence the success or otherwise of a potential vaccine. The objective of this review was to adopt the SWOT concept to elucidate the biological Strengths, Weaknesses, Opportunities, and Threats to Ebola virus as a pathogen, with a view to understanding and devising holistic strategies at combating and overcoming the scourge of EVD. Method: This systematic review and narrative synthesis utilized Medline, PubMed, Google and other databases to select about 150 publications on ebola and ebola virus disease using text word searches to generate the specific terms. Relevant publications were reviewed and compared, findings were synthesized using a narrative method and summarized qualitatively. Results: Some of the identified strengths of ebola virus include: Ebola virus is an RNA virus with inherent capability to mutate, reassort and recombine to generate mutant or reassortant virulent strains; Ebola virus has a broad cellular tropism; Natural Reservoir of ebola virus is unconfirmed but fruit bats, arthropods, and plants are hypothesized; Ebola virus primarily targets and selectively destroys the immune system; Ebola viruses possess accessory proteins that inhibits the host' immune responses; Secreted glycoprotein (sGP), a truncated soluble protein that triggers immune activation and increased vascular permeability is uniquely associated with Ebola virus only; Ability to effectively cross the species barrier and establish productive infection in humans, non human primates, and other mammals; Ebola virus attacks every part of the human body; The Weaknesses include: Ebola virus transmission and persistence is severely limited by its virulence; Ebola virus essentially requires host encoded protein Niemann-Pick C1 (NPC1) for host's cell' entry; Ebola virus essentially requires host encoded proteins (TIM-1) for cell' entry; Relative abundance of Ebolavirus Nucleoprotein than the other virion components; The Opportunities harnessed by ebola virus include: Lack of infection control practices in African health-care facilities and paucity of health infrastructures, especially in the endemic zones; Permissiveness of circulating Monocytes, Macrophages and dendritic cells in virus mobilization and dissemination; Collection, consumption and trade of wild games (bushmeats); Pertubation and drastic changes in forest ecosystems present opportunities for Ebola...

show abstract

Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever

Cited by 240 publications

References 27 publications

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Structure of the Ebola VP35 interferon inhibitory domain

THE STRENGTHS, WEAKNESSES, OPPORTUNITIES, AND THREATS (SWOTs) ANALYSES OF THE EBOLA VIRUS

Contact Info

Product

Resources

About