Biology subjects

Vasquez, S.

Publications and source records attributed to Vasquez, S..

4 recordsLinked to original sources

bioRxiv2026

Developmental and molecular features shaping broad and synergistic actions of human autoantibodies targeting interferon-α

Neutralizing autoantibodies against interferon- (IFN) are associated with severe viral infections but may improve outcomes in IFN-driven autoimmunity. How these antibodies emerge, mature, and function at the molecular level remains unclear. Here, we tracked development of plasma neutralizing activity against all 12 IFNs in multiple human donors over years. Plasma neutralization frequently initiates with narrow IFN specificity, often IFN8, but increases in breadth and potency with individual kinetics. Monoclonal antibody analyses reveal that affinity maturation generates epitope-specific antibody classes, highlighting parallel emergence of subtype-restricted and broadly-reactive antibodies. Biophysical and structural characterization of human antibody-IFN complexes uncovers determinants of initial specificity and breadth development. Strikingly, antibodies engaging non-competing, neutralizing epitopes can act co-operatively to block IFN signaling, and some combinations trigger Fc-effector functions via cell surface IFN:IFNAR2 interactions that may eliminate IFN-responsive cells. Our findings reveal features shaping anti-IFN autoantibody repertoires and unappreciated synergistic mechanisms that amplify their potency and pathogenic potential.

immunology↗

bioRxiv2026

Topographic structure and function of locus coeruleus norepinephrine neurons

Norepinephrine (NE) is released throughout most of the central nervous system by neurons in the locus coeruleus (LC). We found a relationship between the morphologies, gene expression, and activity of LC-NE neurons in mice. Axonal projections of individual neurons were extensive but largely confined to subsets of brain regions. Axonal projections and graded gene expression correlated with locations of cell bodies in LC. In a behavioral task requiring ongoing learning from actions, neurons in dorsal LC projecting to the cerebral cortex were excited when mice made a different choice from the previous one and by reward prediction errors, a signal driving learning. Background activity of neurons in ventral LC was higher when mice ignored stimuli indicating potential reward availability. These observations reveal a topographically organized structure and function of a neurotransmitter system and show that it contains learning signals for flexible behavior.

neuroscience↗

bioRxiv2025

Human Coronavirus HKU1 Neutralizing Monoclonal Antibodies Target Diverse Epitopes Within and Around the TMPRSS2 Receptor Binding Site

Endemic human coronaviruses (HCoVs), such as HCoV-HKU1, account for [~]30% of common colds each year and can cause serious upper and lower respiratory infections, yet no licensed vaccines or therapeutic antibodies target HCoVs. Despite being endemic to the human population, little is known about the antigenic landscape of HCoV-HKU1. Here, we characterized key interactions between the HCoV-HKU1 spike (S) protein and monoclonal antibodies (mAbs) isolated from convalescent HCoV-HKU-1-positive peripheral blood mononuclear cells collected prior to the COVID-19 pandemic. We isolated 14 mAbs that bound distinct regions of S, including the receptor-binding domain (RBD), N-terminal domain, and S2 subunit. Structural and functional studies revealed three groups of RBD-specific mAbs targeting diverse footprints within and around the TMPRSS2 receptor-binding site: (1) H501-022, which recognizes the TMPRSS2-binding site and thereby blocks receptor engagement; (2) H501-008, which binds a distinct epitope outside the TMPRSS2-binding site that is shared with HCoV-OC43; and (3) H501-018, which recognizes both "up" and "down" RBD conformations at a distinct, non-overlapping epitope outside the TMPRSS2-binding site. H501-008 weakly neutralized live HCoV-OC43 in vitro and protected mice against lethal HCoV-OC43 challenge. Notably, the three RBD-specific mAbs potently neutralized HCoV-HKU1 pseudovirus in TMPRSS2-overexpressing cell lines, but exhibited limited neutralizing activity against authentic HCoV-HKU1 infection in primary human airway epithelial cells. Together, these findings structurally define the antigenic landscape within and around the HKU1 receptor-binding site and demonstrate that receptor-binding site recognition alone is insufficient to predict physiologically relevant antibody-mediated neutralization.

microbiology↗

bioRxiv2024

Haspin kinase binds to a nucleosomal DNA supergroove

Phosphorylation of histone H3 threonine 3 (H3T3) by Haspin recruits the chromosomal passenger complex to the inner centromere and ensures proper cell cycle progression through mitosis. The mechanism by which Haspin binds to nucleosomes to phosphorylate H3T3 is not known. We report here cryo-EM structures of the Haspin kinase domain bound to a nucleosome. In contrast with previous structures of histone-modifying enzymes, Haspin solely contacts the nucleosomal DNA, inserting into a supergroove formed by apposing major grooves of two DNA gyres. This unique binding mode provides a plausible mechanism by which Haspin can bind to nucleosomes in a condensed chromatin environment to phosphorylate H3T3. We identify key basic residues in the Haspin kinase domain that are essential for phosphorylation of nucleosomal histone H3 and binding to mitotic chromatin. Our structure is the first of a kinase domain bound to a nucleosome and is the first example of a histone-modifying enzyme that binds to nucleosomes solely through DNA contacts.

biophysics↗