Biology subjects

Hazell, N. C.

Publications and source records attributed to Hazell, N. C..

4 recordsLinked to original sources

bioRxiv2026

Molecular basis for chikungunya virus recognition of a mosquito-specific receptor

Alphaviruses are arthropod-borne viruses that recognize cellular receptors in both vertebrate hosts and mosquito vectors to complete their transmission cycle, yet how they maintain recognition of receptors across evolutionarily divergent host species remains unresolved. Among alphaviruses, chikungunya virus (CHIKV), which is primarily vectored in urban settings by Aedes species mosquitoes, is the most widespread, and causes explosive outbreaks that can involve hundreds of thousands to millions of cases annually. The cell adhesion protein Lachesin is a mosquito-specific cellular receptor for CHIKV and multiple other arthritogenic alphaviruses. The envelope E2-E1 glycoproteins of these alphaviruses broadly recognize Lachesin orthologs from diverse mosquito species, but not other insects or arachnids. Lachesin genetic manipulation to prevent mosquito virus infection without interfering with endogenous receptor function could have a major impact for CHIKV control. Here, we determined high-resolution cryo-electron microscopy (cryo-EM) structures of alphaviruses bound to Aedes albopictus Lachesin. Comparative analysis of Lachesin-bound CHIKV, Semliki Forest virus (SFV), and Middelburg virus (MIDV) revealed that these three genetically divergent viruses use a similar surface to recognize Lachesin domain 1, but with reorganized E2-E1 glycoprotein contact residues. We show that a soluble Ae. albopictus Lachesin receptor decoy protein blocks the E2-E1-mediated entry of CHIKV and other arthritogenic alphaviruses into mammalian cells with greater breadth than a vertebrate receptor MXRA8 decoy and protects against lethal SFV challenge and CHIKV pathogenesis in murine models. Additionally, we identified a naturally occurring single residue Lachesin polymorphism that is found in some Anopheles (malaria vector) mosquitoes, and fully ablates CHIKV E2-E1 recognition, informing strategies for mosquito-targeted genetic interventions that could prevent mosquito vector infection and virus transmission. These findings define distinct determinants of receptor binding in mosquitoes and humans for arthritogenic alphaviruses, with implications for countermeasure development and outbreak preparedness.

microbiology↗

bioRxiv2025

Mechanistic insights and in vivo HIV suppression by the BRD4-targeting small molecule ZL0580

Epigenetic suppression and durable silencing of HIV represent a promising strategy to achieve ART-free remission, consistent with the "block and lock" HIV cure paradigm. BRD4 is a host epigenetic reader and plays a critical role in HIV transcriptional regulation. We previously identified ZL0580, a first-in-class BRD4-selective small molecule distinct from the pan-BET inhibitor JQ1, which induces HIV epigenetic suppression. However, detailed molecular mechanisms, pharmacokinetics (PK), and in vivo HIV-suppressive efficacy of ZL0580 remain undefined. Here, we show that ZL0580 selectively targets BRD4 bromodomain 1 (BD1) through interaction with a key glutamic acid residue (E151), as determined by structural modeling and mutagenesis. Transcriptomic profiling by RNA-seq reveals that ZL0580 and JQ1 induce opposing gene expression programs, consistent with their distinct effects on HIV proviral transcription and latency. In a humanized mouse model of HIV infection, ZL0580 monotherapy, or in combination with ART, potently suppressed active HIV replication, reducing the plasma viremia to nearly undetectable levels, and delayed viral rebound following treatment interruption. Collectively, these findings establish ZL0580 as an epigenetic suppressor of HIV in vivo and provide proof-of-concept for its potential as a "block and lock" HIV cure candidate, warranting further optimization and development.

microbiology↗

bioRxiv2025

mRNA-delivered neutralizing antibodies confer protection against SARS-CoV-2 variant in the lower and upper respiratory tract

Monoclonal antibodies (mAbs) have been developed as effective biological countermeasures against a range of human diseases. The high cost of antibody production and manufacturing limits its clinical application and widespread use. The mRNA-lipid nanoparticle (mRNA-LNP) is a versatile platform for development of vaccines and protein-replacement therapeutics. Since the COVID-19 pandemic, a number of neutralizing mAbs against SARS-CoV-2 have been identified with several being used clinically under emergency authorization. Herein, we report the design and generation of mRNA-LNPs expressing two SARS-CoV-2 neutralizing mAbs, 76E1 and LY1404, which respectively target the viral spike proteins fusion peptide (FP) epitope within the S2 subunit and the receptor-binding domain (RBD) within the S1 subunit. We show a single intramuscular administration of mRNA-LNPs results in efficient LY1404 and 76E1 mAb production in mice which is sustained for 7-14 days. Further, we evaluate the protective efficacy of mRNA-LNP formulations encoding the two antibodies in mouse and hamster models challenged with different SARS-CoV-2 viral strains. The data demonstrate that a single administration of mRNA-LNP encoding the more broadly neutralizing antibody 76E1 confers significant protection against the immune-evasive SARS-CoV-2 Omicron variant BQ.1 in both the upper and lower respiratory tract of the hamsters, indicating its potential impact on limiting both viral disease and viral acquisition. Together, our study expands the potential of the mRNA-LNP platform to deliver therapeutic antibodies for rapid prevention or treatment of pathogenic infections.

microbiology↗

bioRxiv2021

Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant

Emergence of SARS-CoV-2 variants of concern (VOC), including the highly transmissible delta strain, has posed challenges to current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified mRNA vaccine that expresses the more conserved viral nucleoprotein (mRNA-N). We show that mRNA-N alone was able to induce a modest but significant control of SARS-CoV-2 in mice and hamsters. Critically, by combining mRNA-N with the clinically approved S-expressing mRNA vaccine (mRNA-S-2P), we found that combinatorial mRNA vaccination (mRNA-S+N) led to markedly enhanced protection against the SARS-CoV-2 delta variant compared to mRNA-S. In a hamster model, we demonstrated that while mRNA-S alone elicited significant control of the delta strain in the lungs ([~]45-fold reduction in viral loads compared to un-vaccinated control), its effectiveness in the upper respiratory tract was weak, whereas combinatorial mRNA-S+N vaccination induced markedly more robust control of the delta variant infection in the lungs ([~]450-fold reduction) as well as in the upper respiratory tract ([~]20-fold reduction). Immune analyses indicated that induction of N-specific immunity as well as augmented S-specific T-cell response and neutralizing antibody activity were collectively associated the enhanced protection against SARS-CoV-2 delta strain by combinatorial mRNA vaccination. These findings suggest that the combined effects of protection in the lungs and upper respiratory tract could both reduce the risk of severe disease as well as of infection and transmission.

microbiology↗