Biology subjects

Moscona, A.

Publications and source records attributed to Moscona, A..

5 recordsLinked to original sources

bioRxiv2026

Fusion Peptide Insertion Configuration Determines the Mechanism of Membrane Curvature Induction in Human Parainfluenza Virus Type 3

Viral entry requires remodeling the host membrane with a short fusion peptide (FP) that anchors and deforms the target lipid bilayer. However, the contribution of the FP throughout the full fusion pathway remains unknown. Here, all-atom molecular dynamics simulations define the membrane- deformation mechanisms associated with two distinct insertion configurations of membrane-bound human parainfluenza virus type 3 (HPIV3) FP. Molecular simulations quantifying the linear response of curvature to the peptide are complemented with analyses of lipid organization and FP-lipid interactions to define the underlying membrane-deformation mechanisms. The surface-parallel FP configuration generates positive membrane curvature through deformation of the proximal leaflet, consistent with the classical hydrophobic insertion (wedging) mechanism. In contrast, the transmembrane FP configuration generates curvature through localized deformation of the distal leaflet, a distinct mechanism that would strongly influence later stages of fusion. Cryo-electron tomography shows that target membrane curvature at virus-host contact sites is consistent with the molecular dynamics prediction. In the absence of F-protein activation and FP insertion, the cryo-ET-determined curvature distribution shifts toward negative values, thereby isolating the role of the fusion protein in inducing early-stage curvature that enables the host and virus membranes to approach one another. Modeling key mutational changes isolates how aromatic and electrostatic interactions act together to promote curvature generation. Taken together, these findings establish FP insertion configuration as a determinant of productive membrane curvature across the full fusion pathway.

biophysics↗

bioRxiv2025

Stabilized Full-Length Measles Fusion Protein Elicits Potent Immunity and Protection In Vivo

Measles virus (MeV) is a highly contagious pathogen that causes significant morbidity and mortality in populations with low vaccination coverage. Infection typically leads to immune amnesia and, in rare cases, fatal neurological disease. While current live-attenuated vaccines are highly effective, they primarily elicit neutralizing antibodies against the hemagglutinin (H) glycoprotein, with a less robust response to the fusion (F) protein, a key protein for viral entry. To improve the immunogenicity of the F protein, we designed and characterized stabilized, prefusion MeV F protein antigens. We engineered both soluble ectodomains (FECTO) and full-length, membrane-embedded proteins (FFL) with mutations that confer thermal stability. Cryo-electron microscopy confirmed that these engineered antigens faithfully maintain the native prefusion conformation. When evaluated in a cotton rat model, immunization with either FECTO or FFL constructs induced neutralizing antibodies and elicited protection against viral challenge. The most stable full-length construct (FFL 3M) elicited a more potent neutralizing antibody response than its ectodomain counterpart. Importantly, no evidence of vaccine-enhanced respiratory disease was observed. These findings establish that a thermostable, full-length F protein is a superior immunogen to its soluble ectodomain. This work presents a promising candidate for next-generation, non-replicating measles vaccines intended to complement current vaccination strategies and provide a safe option for immunocompromised individuals and others who cannot receive live-virus vaccines. One-Sentence SummaryA prefusion-stabilized, full-length measles Fusion glycoprotein immunogen induces strong neutralizing responses and offers protection against challenge with wild-type virus.

immunology↗

bioRxiv2021

Measles fusion complexes from central nervous system clinical isolates: decreased interaction between hemagglutinin and fusion proteins

Measles virus (MeV) viral entry is mediated by a fusion complex comprised of a receptor binding protein (hemagglutinin, H) and a fusion protein (F). The wild type H/F complex requires interaction with specific proteinaceous receptors (CD150/SLAM and nectin-4) in order to be activated. In contrast the H/F complexes isolated from viruses infecting the central nervous system (CNS) do not require a specific receptor. A single amino acid change in the F protein (L454W) was previously identified in two patients with lethal sequelae of MeV CNS infection, and the F bearing this mutation mediates fusion even without the H protein. We show here that viruses bearing the L454W fusion complex are less efficient than wt virus at targeting receptor expressing cells and that this defect is associated with a decreased interaction between the H and the F proteins. ImportanceMeasles (Mev) infection can cause serious complications including measles inclusion body encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE). MIBE and SSPE are relatively rare but lethal. We have shown that the fusion complex of CNS adapted clinical samples can spread in the absence of known receptor. We now provide evidence that HRC mutations leading to CNS adaptation come at a cost to the efficiency of viral entry. One Sentence SummaryMeasles CNS adapted fusion complexes have altered H/F interaction.

microbiology↗

bioRxiv2021

Engineering protease-resistant peptides to inhibit human parainfluenza viral respiratory infection

The lower respiratory tract infections affecting children worldwide are in large part caused by the parainfluenza viruses (HPIVs), particularly HPIV3, along with human metapneumovirus and respiratory syncytial virus, enveloped negative-strand RNA viruses. There are no vaccines for these important human pathogens, and existing treatments have limited or no efficacy. Infection by HPIV is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. A viral fusion protein (F), once activated in proximity to a target cell, undergoes a series of conformational changes that first extend the trimer subunits to allow insertion of the hydrophobic domains into the target cell membrane, and then refold the trimer into a stable postfusion state, driving the merger of the viral and host cell membranes. Lipopeptides derived from the C-terminal heptad repeat (HRC) domain of HPIV3 F inhibit infection by interfering with the structural transitions of the trimeric F assembly. Clinical application of this strategy, however, requires improving the in vivo stability of antiviral peptides. We show that the HRC peptide backbone can be modified via partial replacement of -amino acid residues with {beta}-amino acid residues to generate /{beta}-peptides that retain antiviral activity but are poor protease substrates. Relative to a conventional -lipopeptide, our best /{beta}-lipopeptide exhibits improved persistence in vivo and improved anti-HPIV3 antiviral activity in animals.

microbiology↗

bioRxiv2020

In vivo antiviral host response to SARS-CoV-2 by viral load, sex, and age

Despite limited genomic diversity, SARS-CoV-2 has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA-sequencing profiles of nasopharyngeal swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with upregulation of antiviral factors such as OAS1-3 and IFIT1-3, and Th1 chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial cultures replicated the in vivo antiviral host response. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of Th1 chemokines CXCL9/10/11 and their cognate receptor, CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B and NK cell-specific transcripts and an increase in inhibitors of NF-{kappa}B signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.

microbiology↗