A5067493639- Influenza Virus Research Studies
- SARS-CoV-2 and COVID-19 Research
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Respiratory viral infections research
- vaccines and immunoinformatics approaches
- interferon and immune responses
- Evolution and Genetic Dynamics
- Viral gastroenteritis research and epidemiology
- Protein Structure and Dynamics
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- RNA modifications and cancer
- RNA Research and Splicing
- Animal Virus Infections Studies
- Viral Infections and Immunology Research
- Advanced biosensing and bioanalysis techniques
- Heat shock proteins research
- COVID-19 Clinical Research Studies
- SARS-CoV-2 detection and testing
- Viral Infections and Vectors
- Immunodeficiency and Autoimmune Disorders
- Fungal and yeast genetics research
- Bat Biology and Ecology Studies
- Bacillus and Francisella bacterial research
University of Illinois Urbana-Champaign
2020-2025
Karolinska Institutet
2021-2023
Nanyang Technological University
2021-2023
An engineered decoy receptor tightly binds S from diverse SARS-related coronaviruses with limited potential for viral escape.
Since the COVID-19 pandemic onset, antibody response to SARS-CoV-2 has been extensively characterized. Antibodies receptor binding domain (RBD) on spike protein are frequently encoded by IGHV3-53/3-66 with a short complementarity-determining region (CDR) H3. Germline-encoded sequence motifs in heavy chain CDRs H1 and H2 have major function, but whether any common present CDR H3, which is often critical for specificity, not clear. Here, we identify two public clonotypes of RBD antibodies...
Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All vaccines in US encode with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering immunogens involve tedious experimental work and heavily rely structural information. Here, we establish a systematic unbiased method identifying that concomitantly improve expression conformation spike. Our integrates fluorescence-based fusion assay,...
Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding spike protein. In contrast, whether antigenic occurs S2 remains largely elusive. Here, we perform a deep mutational scanning experiment to identify that affect three apex public antibodies. Our results indicate spatially diverse mutations, including D950N Q954H, which are observed Delta Omicron variants, respectively, weaken these Although antibodies known be nonneutralizing, show...
Abstract The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane during virus entry and part a broadly neutralizing epitope. However, sequence determinants at the its adjacent regions pathogenicity antigenicity remain elusive. In this study, we perform series deep mutational scanning (DMS) experiments on an S2 region spanning authentic in different cell lines presence antibodies. We identify mutations residue 813 that reduced TMPRSS2-mediated with decreased...
Abstract The receptor-binding site of influenza A virus hemagglutinin partially overlaps with major antigenic sites and constantly evolves. In this study, we observe that mutations G186D D190N in the have coevolved two recent human H3N2 clades. X-ray crystallography results show these coordinately drive evolution receptor binding mode. Epistasis between is further demonstrated by glycan thermostability analyses. Immunization neutralization experiments using mouse samples indicate mode...
Increasing the expression level of SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering receptor-binding domain (RBD) and S2 subunit, amino-terminal (NTD) long overlooked because limited understanding its biophysical constraints. In this study, effects thousands NTD single mutations S were quantified by deep mutational scanning. Our results revealed that in terms expression, tolerability residues was inversely...
Influenza neuraminidase (NA) has received increasing attention as an effective vaccine target. However, its mutational tolerance is not well characterized. Here, the fitness effects of >6,000 mutations in human H3N2 NA are probed using deep scanning. Our result shows that while antigenic regions have high tolerance, there solvent-exposed with low tolerance. We also find protein stability a major determinant fitness. The scanning correlates inferred from natural sequences language model,...
The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence–function maps and constrain the availability adaptive paths. While theoretical intuition often built on global statistics large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood reference genotype. It unclear to what extent local topography real epistatic landscape represents its shape. Here, we demonstrate that landscapes be...
Influenza poses a major health issue globally. Neutralizing antibodies targeting the highly conserved stem region of hemagglutinin (HA) influenza virus provide considerable protection against infection. Using an array advanced simulation technologies, we developed high-resolution structural model full-length, Fab-bound HA in native viral membrane to characterize direct interactions that govern efficacy antibody. We reveal functionally important residues beyond antibody's...
G3BP is the central node within stress-induced protein–RNA interaction networks known as stress granules (SGs). The SG-associated proteins Caprin-1 and USP10 bind mutually exclusively to NTF2 domain of G3BP1, promoting inhibiting SG formation, respectively. Herein, we present crystal structure G3BP1-NTF2 in complex with a Caprin-1-derived short linear motif (SLiM). interacts His-31 His-62 third NTF2-binding site outside those covered by USP10, confirmed using biochemical biophysical-binding...
ABSTRACT The spike S of SARS-CoV-2 recognizes ACE2 on the host cell membrane to initiate entry. Soluble decoy receptors, in which ectodomain is engineered block with high affinity, potently neutralize infection and, due close similarity natural receptor, hold out promise being broadly active against virus variants without opportunity for escape. Here, we directly test this hypothesis. We find an sACE2 2 .v2.4, tightly binds SARS-associated viruses from humans and bats, despite ACE2-binding...
Egg-adaptive mutations in influenza hemagglutinin (HA) often emerge during the production of egg-based seasonal vaccines, which contribute to largest share global vaccine market. While some egg-adaptive have minimal impact on HA antigenicity (e.g. G186V), others can alter it L194P). Here, we show that preference mutation human H3N2 is strain-dependent. In particular, Thr160 and Asn190, are found many recent strains, restrict emergence L194P but not G186V. Our results further suggest natural...
The influenza A virus nuclear export protein (NEP) is a multifunctional that essential for the viral life cycle and has very high sequence conservation. However, since open reading frame of NEP largely overlaps with another protein, non-structural 1, it difficult to infer functional constraints based on conservation analysis. Besides, N-terminal structurally disordered, which further complicates understanding its function. Here, we systematically measured replication fitness effects >1,800...
The ability of the human immune system to generate antibodies any given antigen can be strongly influenced by immunoglobulin V-gene allelic polymorphisms. However, previous studies have provided only limited examples. Therefore, prevalence this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many polymorphisms in antibody paratopes are determinants for binding activity. Biolayer interferometry experiments further demonstrate...
Despite decades of antibody research, it remains challenging to predict the specificity an solely based on its sequence. Two major obstacles are lack appropriate models and inaccessibility datasets for model training. In this study, we curated a dataset >5,000 influenza hemagglutinin (HA) antibodies by mining research publications patents, which revealed many distinct sequence features between HA head stem domains. We then leveraged develop lightweight memory B cell language (mBLM)...
Abstract Since the COVID-19 pandemic onset, antibody response to SARS-CoV-2 has been extensively characterized. Antibodies receptor binding domain (RBD) on spike protein are frequently encoded by IGHV3-53/3-66 with a short CDR H3. Germline-encoded sequence motifs in CDRs H1 and H2 play major role, but whether any common present H3, which is often critical for specificity, have not elucidated. Here, we identify two public clonotypes of RBD antibodies 9-residue H3 that pair different light...
The antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for development vaccines capable eliciting long-term protection. Prior efforts to understand mechanisms that govern viral mainly focus on HA in isolation, ignoring fact must act concert with neuraminidase (NA) during replication and spread. Numerous studies have demonstrated degree which receptor-binding avidity receptor-cleaving activity NA are balanced each other influences overall fitness. We...