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TitleProtective human monoclonal antibodies target conserved sites of vulnerability on the underside of influenza virus neuraminidase.
Journal, issue, pagesImmunity, Vol. 57, Issue 3, Page 574-586.e7, Year 2024
Publish dateMar 12, 2024
AuthorsJulia Lederhofer / Yaroslav Tsybovsky / Lam Nguyen / Julie E Raab / Adrian Creanga / Tyler Stephens / Rebecca A Gillespie / Hubza Z Syeda / Brian E Fisher / Michelle Skertic / Christina Yap / Andrew J Schaub / Reda Rawi / Peter D Kwong / Barney S Graham / Adrian B McDermott / Sarah F Andrews / Neil P King / Masaru Kanekiyo /
PubMed AbstractContinuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the ...Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that target the underside of the NA globular head domain, inhibit viral propagation of a wide range of human H3N2, swine-origin variant H3N2, and H2N2 viruses, and confer both pre- and post-exposure protection against lethal H3N2 infection in mice. Cryo-EM structures of two such antibodies in complex with NA reveal non-overlapping epitopes covering the underside of the NA head. These sites are highly conserved among N2 NAs yet inaccessible unless the NA head tilts or dissociates. Our findings help guide the development of effective countermeasures against ever-changing influenza viruses by identifying hidden conserved sites of vulnerability on the NA underside.
External linksImmunity / PubMed:38430907 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.6 Å
Structure data

29907

8gat

EMDB-29907: Structure of human NDS.1 Fab and 1G01 Fab in complex with influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v); consensus map with only Fab 1G01 resolved
PDB-8gat: Structure of human NDS.1 Fab and 1G01 Fab in complex with influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v), based on consensus cryo-EM map with only Fab 1G01 resolved
Method: EM (single particle) / Resolution: 3.0 Å

29908

8gau

EMDB-29908: Structure of human NDS.1 Fab and 1G01 Fab in complex with influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v), locally refined map
PDB-8gau: Structure of human NDS.1 Fab and 1G01 Fab in complex with influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v)
Method: EM (single particle) / Resolution: 3.6 Å

29909

8gav

EMDB-29909, PDB-8gav:
Structure of human NDS.3 Fab in complex with influenza virus neuraminidase from A/Darwin/09/2021 (H3N2)
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • influenza a virus (a/indiana/10/2011(h3n2))
  • influenza a virus
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / neuraminidase / antibody / influenza / VIRAL PROTEIN-IMMUNE SYSTEM complex

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