Biology subjects

Hastie, K. M.

Publications and source records attributed to Hastie, K. M..

4 recordsLinked to original sources

bioRxiv2022

Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

The mammarenavirus Lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and cause severe birth defects if acquired during pregnancy. Despite the fundamental importance of LCMV for studying immunobiology, the structure of the trimeric surface glycoprotein, essential for entry, vaccine design and antibody neutralization, remains unknown. In this study, we present the cryoEM structure of the LCMV surface glycoprotein (GP) in its trimeric prefusion assembly both alone and in complex with a rationally engineered monoclonal neutralizing antibody termed 18.5C-M28 (M28). Additionally, we show that passive administration of M28 protects mice from LCMV clone 13 (LCMVcl13) challenge when administered as either a prophylactic or therapeutic. Our study illuminates not only the overall structural organization of LCMV GP and the mechanism for its inhibition by M28, but also presents a promising therapeutic candidate to prevent severe or fatal disease in individuals who are at risk of infection by a virus that poses a threat worldwide. HighlightsO_LIRationally-engineered antibody M28 neutralizes lymphocytic choriomeningitis virus in vitro. C_LIO_LIFirst high-resolution cryoEM structure of the pre-fusion trimeric lymphocytic choriomeningitis virus glycoprotein alone and in complex with M28. C_LIO_LIM28 neutralizes by bridging adjacent glycoprotein protomers and locking it in the pre-fusion state. C_LIO_LIProphylactic and therapeutic administration of M28 protects mice from chronic lymphocytic choriomeningitis virus infection. C_LI

microbiology↗

bioRxiv2021

Structure of the rabies virus glycoprotein trimer bound to a pre-fusion specific neutralizing antibody

Rabies infection is nearly 100% lethal if untreated and kills over 50,000 people annually, many of them children. Existing rabies vaccines target the rabies virus glycoprotein (RABV-G) but generate short-lived immune responses, likely because the protein is heterogeneous under physiological conditions. Here, we report the 3.39[A] cryo-EM structure of trimeric, pre-fusion RABV-G complexed with RVA122, a potently neutralizing human antibody. RVA122 binds to a quaternary epitope at the top of RABV-G, bridging domains and stabilizing RABV-G protomers in a prefusion state. RABV-G trimerization involves side-to-side interactions between the central -helix and adjacent loops, rather than contacts between central helices, and interactions among the fusion loops at the glycoprotein base. These results provide a basis to develop improved rabies vaccines based on RABV-G stabilized in the prefusion conformation. One sentence summaryWe report the structure and trimeric interface of pre-fusion rabies virus glycoprotein bound to the neutralizing antibody RVA122.

microbiology↗

bioRxiv2021

Molecular assembly of measles and Nipah virus: specific lipid binding drives conformational change and matrix polymerization

Measles virus, Nipah virus, and multiple other paramyxoviruses cause disease outbreaks in humans and animals worldwide. The paramyxovirus matrix (M) protein mediates virion assembly and budding from host cell membranes. M is thus a key target for antivirals, but few high-resolution structures of paramyxovirus M are available, and we lack the clear understanding of how viral M proteins interact with membrane lipids to mediate viral assembly and egress needed to guide antiviral design. Here, we reveal that M proteins associate with phosphatidylserine and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) at the plasma membrane. Using X-ray crystallography, electron microscopy, and molecular dynamics we demonstrate that PI(4,5)P2 binding induces conformational and electrostatic changes in the M protein surface that trigger membrane deformation, matrix layer polymerization, and virion assembly.

microbiology↗

bioRxiv2020

Immunological memory to SARS-CoV-2 assessed for greater than six months after infection

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at [≥] 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

immunology↗