Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease

Misasi, John; Sullivan, Nancy J.

doi:10.1016/j.cell.2014.10.006

Cited by 67 publications

(76 citation statements)

References 121 publications

(160 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…bola virus (EBOV) is a nonsegmented negative-sense RNA virus that belongs to the family Filoviridae, which consists of three genera: Marburgvirus, Ebolavirus, and Cuevavirus (1). EBOV causes severe hemorrhagic fever in humans, with a fatality rate of up to 90% (2).…”

mentioning

confidence: 99%

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Lingemann

Liu

Surman

et al. 2017

J Virol

View full text Add to dashboard Cite

The recent 2014-2016 Ebola virus (EBOV) outbreak prompted increased efforts to develop vaccines against EBOV disease. We describe the development and preclinical evaluation of an attenuated recombinant human parainfluenza virus type 1 (rHPIV1) expressing the membrane-anchored form of EBOV glycoprotein GP, as an intranasal (i.n.) EBOV vaccine. GP was codon optimized and expressed either as a full-length protein or as an engineered chimeric form in which its transmembrane and cytoplasmic tail (TMCT) domains were replaced with those of the HPIV1 F protein in an effort to enhance packaging into the vector particle and immunogenicity. GP was inserted either preceding the N gene (pre-N) or between the N and P genes (N-P) of rHPIV1 bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ). The constructs grew to high titers and efficiently and stably expressed GP. Viruses were attenuated, replicating at low titers over several days, in the respiratory tract of African green monkeys (AGMs). Two doses of candidates expressing GP from the pre-N position elicited higher GP neutralizing serum antibody titers than the N-P viruses, and unmodified GP induced higher levels than its TMCT counterpart. Unmodified EBOV GP was packaged into the HPIV1 particle, and the TMCT modification did not increase packaging or immunogenicity but rather reduced the stability of GP expression during in vivo replication. In conclusion, we identified an attenuated and immunogenic i.n. vaccine candidate expressing GP from the pre-N position. It is expected to be well tolerated in humans and is available for clinical evaluation.IMPORTANCE EBOV hemorrhagic fever is one of the most lethal viral infections and lacks a licensed vaccine. Contact of fluids from infected individuals, including droplets or aerosols, with mucosal surfaces is an important route of EBOV spread during a natural outbreak, and aerosols also might be exploited for intentional virus spread. Therefore, vaccines that protect against mucosal as well as systemic inoculation are needed. We evaluated a version of human parainfluenza virus type 1 (HPIV1) bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ) as an intranasal vaccine vector to express the EBOV glycoprotein GP. We evaluated expression from two different genome positions (pre-N and N-P) and investigated the use of vector packaging signals. African green monkeys immunized with two doses of the vector expressing GP from the pre-N position developed high titers of GP neutralizing serum antibodies. The attenuated vaccine candidate is expected to be safe and immunogenic and is available for clinical development.

show abstract

mentioning

confidence: 99%

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Lingemann

Liu

Surman

et al. 2017

J Virol

View full text Add to dashboard Cite

show abstract

“…In addition, VP24 prevents the nuclear accumulation of dimerized phosphorylated STAT-1 that participates in activation of both type I and type II signalling cascades [13,23,27]. It is possible that the negatively selected VP24 sites, 55 and 133, might aid the EBOV to become more pathogenic to human by inhibiting IFN response and blocking antigen presentation to T-cells [18]. Importantly, considering these two negatively selected VP24 amino acids include in the T-cell epitopes which can be used for vaccine design and testing.…”

Section: Discussionmentioning

confidence: 99%

“…The EBOV genome consists of seven genes such as nucleoprotein (NP), the membrane-associated viral protein (VP24), polymerase matrix viral proteins (VP30 and VP35), matrix viral protein (VP40), the RNA-dependent RNA polymerase (L), and the glycoprotein (GP), which are transcribed into mRNA, resulting in the production of at least ten proteins [15,18]. Notably, gene GP encodes two proteins, namely secreted glycoprotein (sGP) and small secreted glycoprotein (ssGP), as a result of mRNA editing.…”

Section: Sequence Selectionmentioning

confidence: 99%

“…Due to the acute effect on the host immune system, recovery time of EBOV infected individual is a lengthy and complex process. EBOV targets the dendritic cells, monocytes and macrophages during the early stages of infection, while, non-lymphocytic cell types at the later stages [18,19]. As there are no effective vaccines and anti-viral therapies available for EBOV, serious efforts are being taken to develop the same in order to prevent infection and cure the disease [7].…”

Section: Introductionmentioning

confidence: 99%

“…facilitates dominated virus replication and progeny transmission [18]. Further advancement in the understanding of host-viral interactions is pertinent and beneficial to subsequently limiting and eliminating EBOV infections.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ebolavirus evolves in human to minimize the detection by immune cells by accumulating adaptive mutations

Ramaiah

Arumugaswami

2016

VirusDis.

View full text Add to dashboard Cite

The current outbreak of Zaire ebolavirus (EBOV) lasted longer than the previous outbreaks and there is as yet no proven treatment or vaccine available. Understanding host immune pressure and associated EBOV immune evasion that drive the evolution of EBOV is vital for diagnosis as well as designing a highly effective vaccine. The aim of this study was to deduce adaptive selection pressure acting on each amino acid sites of EBOV responsible for the recent 2014 outbreak. Multiple statistical methods employed in the study include SLAC, FEL, REL, IFEL, FUBAR and MEME. Results show that a total of 11 amino acid sites from sGP and ssGP, and 14 sites from NP, VP40, VP24 and L proteins were inferred as positively and negatively selected, respectively. Overall, the function of 11 out of 25 amino acid sites under selection pressure exactly found to be involved in T cell and B-cell epitopes. We identified that the EBOV had evolved through purifying selection pressure, which is a predictor that is known to aid the virus to adapt better to the human host and subsequently reduce the efficiency of existing immunity. Furthermore, computational RNA structure prediction showed that the three synonymous nucleotide mutations in NP gene altered the RNA secondary structure and optimal base-pairing energy, implicating a possible effect on genome replication. Here, we have provided evidence that the EBOV strains involved in the recent 2014 outbreak have evolved to minimize the detection by T and B cells by accumulating adaptive mutations to increase the survival fitness.

show abstract

The induction and characterization of monoclonal antibodies specific to GP of Ebola virus

Tian

Chen

Wang

et al. 2020

Journal of Medical Virology

View full text Add to dashboard Cite

The Ebola virus is highly infectious and characterized by hemorrhagic fever, headache, and so on with a high mortality rate. Currently, there are neither therapeutic drugs or vaccines against the Ebola virus nor fast diagnostic methods for the detection of Ebola virus infection. This study reported the induction and isolation of two monoclonal antibodies that specifically recognized the glycoprotein (GP) and secreted glycoprotein (sGP) of the Ebola virus. Plasmids encoding either GP or sGP were constructed and immunized BALB/c mice, accordingly purified sGP was boosted. The antisera were analyzed for binding activity against sGP protein in enzyme‐linked immunosorbent assay (ELISA) and neutralization activity in a pseudotyped virus neutralization assay. A number of reactive clones were isolated and two monoclonal antibodies T231 and T242 were identified to react with both GP and sGP. Western blot and ELISA assays showed that the monoclonal antibodies could react with GP and sGP, respectively. Moreover, they could recognize Ebola pseudovirus by cellular immunochemistry assay. We labeled the monoclonal antibody T231 with biotin and analyzed the competitiveness of the two antibodies by the ELISA test. The results showed that the binding epitopes of the two monoclonal antibodies to sGP were partially overlapped. In summary, two GP‐specific mAbs were identified, which will be used to detect the Ebola virus or investigate GP.

show abstract

Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease

Cited by 67 publications

References 121 publications

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Ebolavirus evolves in human to minimize the detection by immune cells by accumulating adaptive mutations

The induction and characterization of monoclonal antibodies specific to GP of Ebola virus

Contact Info

Product

Resources

About