Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes

Kallewaard, Nicole L.; Corti, Davide; Collins, Patrick J.; Neu, Ursula; McAuliffe, Josephine M.; Benjamin, Emelia J.; Wachter-Rosati, Leslie; Palmer-Hill, Frances J.; Yuan, Andy Q.; Walker, P.A.; Vorlaender, Matthias K.; Bianchi, Siro; Guarino, Barbara; Marco, Anna De; Vanzetta, Fabrizia; Agatic, Gloria; Foglierini, Mathilde; Pinna, Debora; Fernandez-Rodriguez, Blanca; Fruehwirth, Alexander; Silacci, Chiara; Ogrodowicz, R.W.; Martin, Stephen R.; Sallusto, Federica; Suzich, JoAnn; Lanzavecchia, Antonio; Zhu, Qing; Gamblin, S.J.; Skehel, J.J.

doi:10.1016/j.cell.2016.05.073

Cited by 330 publications

(367 citation statements)

References 32 publications

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“…Currently, mAbs have been approved or are in development for numerous infectious diseases, including RSV, influenza, Pseudomonas aeruginosa, and Staphylococcus aureus (18,20,(29)(30)(31)(32). These mAbs target secreted virulence factors, surface/structural proteins, or both, resulting in neutralization of pathogen-induced host damage and improved pathogen clearance.…”

Section: Discussionmentioning

confidence: 99%

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Cohen¹,

Pelletier²,

Cheng³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Cohen¹,

Pelletier²,

Cheng³

et al. 2017

JCI Insight

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“…In fact, two group 2-specific stem-binding bnAbs, namely CR8020 [107] and CR8043 [109], find a solution by recognizing an epitope lower down the stem, which may avoid a direct clash with the oligosaccharide at Asn38. Another stem-binding bnAb MEDI8852 binds to an epitope slightly higher than that of CR8020 and CR8043 and can neutralize both group 1 and 2 subtypes [105]. These bnAbs do not use V H 1–69 germline gene.…”

Section: Functionally Conserved Region 2: Membrane Fusionmentioning

confidence: 99%

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Wilson

2017

Journal of Molecular Biology

137

169

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Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin glycoprotein (HA), which is the major antigen on the surface of the virus. The HA is comprised of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino-acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site (RBS) and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines as well as novel therapeutics.

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“…The IFL and HR1 are seemingly well exposed on the surface of the GP, similar to other enveloped viruses for which these features have been identified as sites of vulnerability for broadly neutralizing antibodies (Kallewaard et al, 2016; Kong et al, 2016. Nevertheless, antibodies that target the IFL are isolated at a low frequency.…”

Section: Discussionmentioning

confidence: 80%

Structural Basis of Pan-Ebolavirus Neutralization by an Antibody Targeting the Glycoprotein Fusion Loop

et al. 2018

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SUMMARY Monoclonal antibodies (mAbs) with pan-ebolavirus cross-reactivity are highly desirable, but development of such mAbs is limited by a lack of a molecular understanding of cross-reactive epitopes. The anti body ADI-15878 was previously identified from a human survivor of Ebola virus Makona variant (EBOV/ Mak) infection. This mAb demonstrated potent neutralizing activity against all known ebolaviruses and provided protection in rodent and ferret models against three ebolavirus species. Here, we describe the unliganded crystal structure of ADI-15878 as well as the cryo-EM structures of ADI-15878 in complex with the EBOV/Mak and Bundibugyo virus (BDBV) glycoproteins (GPs). ADI-15878 binds through an induced-fit mechanism by targeting highly conserved residues in the internal fusion loop (IFL), bridging across GP protomers via the heptad repeat 1 (HR1) region. Our structures provide a more complete description of the ebolavirus immunogenic landscape, as well as a molecular basis for how rare but potent antibodies target conserved filoviral fusion machinery.

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Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes

Cited by 330 publications

References 32 publications

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

Anti-LPS antibodies protect against Klebsiella pneumoniae by empowering neutrophil-mediated clearance without neutralizing TLR4

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Structural Basis of Pan-Ebolavirus Neutralization by an Antibody Targeting the Glycoprotein Fusion Loop

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