Biology subjects

Ols, S.

Publications and source records attributed to Ols, S..

4 recordsLinked to original sources

bioRxiv2026

Structural and functional characterization of polyclonal antibody responses reveals shared and distinct antigenic features of RSV and hMPV fusion proteins

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), members of the Pneumoviridae family, circulate widely and are leading causes of hospitalization for acute respiratory infections in infants and older adults. The viral fusion (F) protein in its prefusion (preF) conformation is the primary target of neutralizing antibodies, yet how naturally elicited circulating polyclonal antibodies are distributed across its antigenic landscape remains poorly understood. Here, we combined serological profiling, site-specific antibody competition assays and electron microscopy-based polyclonal epitope mapping (EMPEM) to characterize preF-directed immunity to RSV and hMPV in healthy adults. All donors exhibited detectable preF-binding antibodies that positively correlated with virus neutralization and broadly recognized multiple antigenic sites, consistent with immunodominance patterns predicted by a surface-centric computational model. Despite this overall similarity, the distribution of responses across individual antigenic sites differed between RSV and hMPV. EMPEM analyses revealed consistent targeting of the highly neutralization-sensitive preF apex (site O) in both viruses, alongside less abundant responses against equatorial and upper-middle epitopes (sites II, III, IV and V). We additionally observed antibody-bound destabilized preF, supporting a model in which antibody binding promotes transient opening of the preF trimer and may interfere with the conformational rearrangements required for membrane fusion. Together, these findings highlight apex-directed antibodies as a prominent feature of naturally acquired pneumovirus immunity in adults and reveal both shared and distinct patterns of antigenic recognition that may inform next-generation vaccine design and antibody-based prophylactics.

immunology↗

bioRxiv2026

Distinct mechanisms of neutralization by antibodies targeting a conserved pneumovirus F epitope

Pneumoviruses cause seasonal outbreaks leading to hospitalizations of vulnerable populations such as infants and the elderly. Cross-neutralizing antibodies targeting viral fusion have been isolated from infected individuals, but their elicitation and mechanisms of action remain understudied. Here, we describe two vaccine-elicited antibody classes, LOR24 and LOR69, that bind an overlapping epitope, and identify the somatic mutations that endow their breadth and potency, respectively. Cryo-electron microscopy structures of both antibodies bound to the HRSV fusion (F) protein show binding modes distinct from each other and from the previously described cross-neutralizing antibody MPE8, yet they all use similar motifs for binding. Complementary in vitro and electron microscopy experiments show that these antibodies either lock prefusion F as a trimer, arrest F in a monomeric or intermediate state, or promote the transition to the postfusion conformation. This work sheds light on mechanisms of pneumovirus neutralization and the elicitation of cross-neutralizing antibody responses.

immunology↗

bioRxiv2024

Computational design of bifaceted protein nanomaterials with tailorable properties

Recent advances in computational methods have led to considerable progress in the design of self-assembling protein nanoparticles. However, nearly all nanoparticles designed to date exhibit strict point group symmetry, with each subunit occupying an identical, symmetrically related environment. This limits the structural diversity that can be achieved and precludes anisotropic functionalization. Here, we describe a general computational strategy for designing multi-component bifaceted protein nanomaterials with two distinctly addressable sides. The method centers on docking pseudosymmetric heterooligomeric building blocks in architectures with dihedral symmetry and designing an asymmetric protein-protein interface between them. We used this approach to obtain an initial 30-subunit assembly with pseudo-D5 symmetry, and then generated an additional 15 variants in which we controllably altered the size and morphology of the bifaceted nanoparticles by designing de novo extensions to one of the subunits. Functionalization of the two distinct faces of the nanoparticles with de novo protein minibinders enabled specific colocalization of two populations of polystyrene microparticles coated with target protein receptors. The ability to accurately design anisotropic protein nanomaterials with precisely tunable structures and functions could be broadly useful in applications that require colocalizing two or more distinct target moieties.

bioengineering↗

bioRxiv2023

Cell targeting and immunostimulatory properties of a novel Fcγ-receptor independent agonistic anti-CD40 antibody in rhesus macaques

Targeting CD40 by agonistic antibodies used as vaccine adjuvants or for cancer immunotherapy is a strategy to stimulate immune responses. The majority of studied agonistic anti-human CD40 antibodies require crosslinking of their Fc region to inhibitory Fc{gamma}RIIb to induce immune stimulation although this has been associated with toxicity in previous studies. Here we introduce an agonistic anti-human CD40 monoclonal IgG1 antibody (MAB273) unique in its specificity to the CD40L binding site of CD40 but devoid of Fc{gamma}-receptor binding, we demonstrate rapid binding of MAB273 to B cells and dendritic cells resulting in strong activation in vitro on human cells and in vivo in rhesus macaques. Dissemination of fluorescently labeled MAB273 after subcutaneous administration was found predominantly at the site of injection and specific draining lymph nodes. Phenotypic cell differentiation and upregulation of genes associated with immune activation were found in the targeted tissues. Antigen-specific T cell responses were enhanced by MAB273 when given in a prime-boost regimen and for boosting low preexisting responses. MAB273 may therefore be a promising immunostimulatory adjuvant that warrants future testing for therapeutic and prophylactic vaccination strategies.

immunology↗