Structural basis for broad neutralization of ebolaviruses by an antibody targeting the glycoprotein fusion loop

Janus, Benjamin M.; Dyk, Nydia van; Zhao, Xuelian; Howell, Katie A.; Soto, Cinque; Aman, M. Javad; Li, Yuxing; Fuerst, Thomas R.; Ofek, Gilad

doi:10.1038/s41467-018-06113-4

Cited by 26 publications

(28 citation statements)

References 37 publications

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“…S1), and it has been well-defined in several reported GP crystal structures ( Fig. 2B, 2C) [28][29][30]. The GP2 glycosylations Ngly563 and Ngly618 are important for GP processing, although they are not necessary for EBOV 293T cell transduction [31].…”

Section: Glycosylation In the Vicinity Of The A28v Substitution Sitementioning

confidence: 69%

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Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona

Lasala

Luczkowiak

Kremer

et al. 2019

Preprint

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Since its discovery in Zaire in 1976, most ebolavirus outbreaks described occurred mainly in remote and poorly communicated areas of Central Africa and affected a limited number of individuals. Nonetheless, the Ebola epidemic that began in West Africa at the end of 2013 spread rapidly and reached an unprecedented scale. This epidemic was caused by the Makona variant of Zaire ebolavirus (EBOV). Monitoring of the EBOV Makona evolution throughout the epidemic identified the A82V substitution in the EBOV glycoprotein (GP) at the beginning of the epidemic, which correlated with its rapid spread. The Makona GP-V82 variant exhibits slightly higher human and primate cell infectivity. Host factors responsible for the enhanced transmission of EBOV Makona have yet to be identified. Here we show that the GP A82V substitution increases EBOV avidity for its DC-SIGN lectin receptor, which enhances cell-binding and infectivity of dendritic cells and macrophages, the primary cell subsets infected during the initial stages of the disease. Using a pseudotype lentivirus system, we identified two GP N-linked glycosylation responsible of the augmented Makona GP-V82 cell infection. Crystal structures indicated how the GP A82V substitution drives exposure of a key glycan and facilitates lectin recognition. Thus, DC-SIGN might be an important host determinant for the unique dissemination of EBOV during the 2013-2016 epidemic, which likely promoted host-to-host transmission by enhancing viral infection of dendritic cells in the skin and mucosa. This study also reveals that variations in virus envelope glycosylations can be a common pathway for virus adaptation to human transmission. Synopsis The Zaire ebolavirus (EBOV) Makona, responsible of the largest outbreak of Ebola virus disease (EVD) in West Africa from 2013-2016, displayed a glycosylation-dependent enhancement of binding and subsequent infectivity in cells expressing the DC-SIGN surface lectin.

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Section: Glycosylation In the Vicinity Of The A28v Substitution Sitementioning

confidence: 69%

“…The glycan is partially recognized by the KZ52 neutralizing Ab (PDB code 3CSY) [29], and it likely protects the fusion loop from antibody recognition. The other N-linked glycans in the GP have high inherent flexibility in the crystal structures [28][29][30];…”

Section: Glycosylation In the Vicinity Of The A28v Substitution Sitementioning

confidence: 99%

Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona

Lasala

Luczkowiak

Kremer

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The watch list can still be expanded if more experimental structures of EBOV -antibody complexes become available. In fact, as we were preparing this manuscript, the crystal structure of mAb CA45 bound to GP1 and GP2 interface of EBOV GP were published by Janus et al [25] Lastly, we believe our in-silico approach could be applied to determine watch lists for other viruses provided experimental structures are available and for future design and optimization efforts of antibodies. 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 Supporting information S1 File.…”

Section: Resultsmentioning

confidence: 86%

Expanding the watch list for potential Ebola virus antibody escape mutations

Patel

Quates

Johnson

et al. 2019

Preprint

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The 2014 outbreak of Ebola virus (EBOV) in Western Africa is the largest recorded filovirus disease outbreak and lead to the death of over 11,000 people. This deadly virus still poses a grave epidemic threat as evidenced by the current (since May 2018) EBOV outbreak in the Democratic Republic of the Congo which has already claimed the lives of over 250 people. One important strategy for combating EBOV epidemics is to anticipate how the evolution of EBOV might undermine treatment since the development of vaccines and antibody therapies are typically based on a single strain (often the 1976 Mayinga) of the EBOV envelope glycoprotein (GP). In a previous study we initiated a watch list of potential antibody escape mutations of EBOV by modeling interactions between EBOV GP and the monoclonal antibody KZ52. This watch list was generated using molecular modeling to estimate the effect of every possible mutation of GP. The final watch list containing 34 mutations were predicted to disrupt GP-KZ52 binding but not to disrupt the ability of GP to fold and to form trimers. In this study, we expand our watch list by including three more monoclonal antibodies with distinct epitopes on GP, namely Antibody 100 (Ab100), Antibody 114 (Ab114) and 13F6-1-2. Our updated watch list contains 127 mutations, three of which have been seen in humans or are experimentally associated with reduced efficacy of antibody treatment. We believe mutations on this broad watch list require attention since they may be a signal of an evolutionary response from EBOV to treatment that could diminish the effectiveness of interventions.

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“…The watch list can still be expanded if more experimental structures of EBOV–antibody complexes become available. In fact, as we were preparing this manuscript, the crystal structure of mAb CA45 bound to GP1 and GP2 interface of EBOV GP were published by Janus et al[ 28 ] Lastly, we believe our in-silico approach could be applied to determine watch lists for other viruses provided experimental structures are available and for future design and optimization efforts of antibodies.…”

Section: Resultsmentioning

confidence: 97%

Expanding the watch list for potential Ebola virus antibody escape mutations

et al. 2019

View full text Add to dashboard Cite

The 2014 outbreak of Ebola virus disease (EVD) in Western Africa is the largest recorded filovirus disease outbreak and led to the death of over 11,000 people. The recent EVD outbreaks (since May 2018) in the Democratic Republic of the Congo has already claimed the lives of over 250 people. Tackling Ebola virus (EBOV) outbreaks remains a challenge. Over the years, significant efforts have been put into developing vaccines or antibody therapies which rely on an envelope glycoprotein (GP) of Zaire ebolavirus (strain Mayinga-76). Therefore, one key approach for combating EVD epidemics is to predict mutations that may diminish the effectiveness of the treatment. In a previous study we generated a watch list of potential antibody escape mutations of EBOV GP against the monoclonal antibody KZ52. Molecular modeling methods were applied to the three-dimensional experimental structure of EBOV GP bound to KZ52 to predict the effect of every possible single mutation in EBOV GP. The final watch list contained 34 mutations that were predicted to destabilize binding of KZ52 to EBOV GP but did not affect EBOV GP folding and its ability to form trimers. In this study, we expand our watch list by including three more monoclonal antibodies with distinct epitopes on GP, namely Antibody 100 (Ab100), Antibody 114 (Ab114) and 13F6-1-2. Our updated watch list contains 127 mutations, three of which have been seen in humans or are experimentally associated with reduced efficacy of antibody treatment. We believe mutations on this watch list require attention since they provide information about circumstances in which interventions could lose the effectiveness.

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Structural basis for broad neutralization of ebolaviruses by an antibody targeting the glycoprotein fusion loop

Cited by 26 publications

References 37 publications

Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona

Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona

Expanding the watch list for potential Ebola virus antibody escape mutations

Expanding the watch list for potential Ebola virus antibody escape mutations

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