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Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections pose a significant health burden. Using pre-fusion conformation fusion (F) proteins, we isolated a panel of anti-F antibodies from a human donor. One antibody (RSV-199) potently cross-neutralized 8 RSV and hMPV strains by recognizing antigenic site III, which is partially conserved in RSV and hMPV F. Next, we determined the cryoelectron microscopy (cryo-EM) structures of RSV-199 bound to RSV F trimers, hMPV F monomers, and an unexpected dimeric form of hMPV F. These structures revealed how RSV-199 engages both RSV and hMPV F proteins through conserved interactions of the antibody heavy-chain variable region and how variability within heavy-chain complementarity-determining region 3 (HCDR3) can be accommodated at the F protein interface in site-III-directed antibodies. Furthermore, RSV-199 offered enhanced protection against RSV A and B strains and hMPV in cotton rats. These findings highlight the mechanisms of broad neutralization and therapeutic potential of RSV-199. ▪ • RSV-199 potently cross-neutralized 8 different RSV and hMPV strains • Cryo-EM reveals RSV-199 targeting antigenic site III of pre-fusion F • RSV-199 mediates enhanced protection in vivo against RSV A and B strains and hMPV • RSV-199 exhibited potencies comparable with RSV or hMPV mono-specific antibodies Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause widespread and significant infections, particularly in children and the elderly. Wen et al. describe a naturally occurring human monoclonal antibody RSV-199 that recognizes, neutralizes, and protects against both RSV and hMPV. [ABSTRACT FROM AUTHOR]

Summary: The conserved multifunctional protein Gle1 regulates gene expression at multiple steps: nuclear mRNA export, translation initiation, and translation termination. A GLE1 mutation (Fin Major ) is causally linked to human lethal congenital contracture syndrome-1 (LCCS1); however, the resulting perturbations on Gle1 molecular function were unknown. Fin Major results in a proline-phenylalanine-glutamine peptide insertion within the uncharacterized Gle1 coiled-coil domain. Here, we find that Gle1 self-associates both in vitro and in living cells via the coiled-coil domain. Electron microscopy reveals that high-molecular-mass Gle1 oligomers form ∼26 nm diameter disk-shaped particles. With the Gle1-FinMajor protein, these particles are malformed. Moreover, functional assays document a specific requirement for proper Gle1 oligomerization during mRNA export, but not for Gle1’s roles in translation. These results identify a mechanistic step in Gle1’s mRNA export function at nuclear pore complexes and directly implicate altered export in LCCS1 disease pathology. [Copyright &y& Elsevier]

Dengue is a major public health threat. There are four dengue virus (DENV) serotypes; therefore, efforts are focused on developing safe and effective tetravalent DENV vaccines. While neutralizing antibodies contribute to protective immunity, there are still important gaps in understanding of immune responses elicited by dengue infection and vaccination. To that end, here, we develop a computational modeling framework based on the concept of antibody-virus neutralization fingerprints in order to characterize samples from clinical studies of TAK-003, a tetravalent vaccine candidate currently in phase 3 trials. Our results suggest a similarity of neutralizing antibody specificities in baseline-seronegative individuals. In contrast, amplification of pre-existing neutralizing antibody specificities is predicted for baseline-seropositive individuals, thus quantifying the role of immunologic imprinting in driving antibody responses to DENV vaccines. The neutralization fingerprinting analysis framework presented here can contribute to understanding dengue immune correlates of protection and help guide further vaccine development and optimization., Competing Interests: Declaration of interests This research was supported by Takeda. Serum from DEN-205 trial (30 samples from 20 donors) and funding were provided by Takeda to support Vanderbilt University Medical Center’s evaluation of the NFP algorithm. I.S.G. is a co-founder of AbSeek Bio. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. L.K. is an employee of Takeda Vaccines, Inc. S.D. and H.J.D. were employees of Takeda Vaccines, Inc., at the time these studies were performed. H.J.D. is a consultant for Takeda Vaccines, Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)