Biology subjects

Ying, B.

Publications and source records attributed to Ying, B..

25 records · Page 2Linked to original sources

bioRxiv2021

Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains

Although mRNA vaccines prevent COVID-19, variants jeopardize their efficacy as immunity wanes. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike) or modified (mRNA-1273.351, designed for B.1.351 spike) preclinical Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Immunization with high or low dose formulations of mRNA vaccines induced neutralizing antibodies in serum against ancestral SARS-CoV-2 and several variants, although levels were lower particularly against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. Nonetheless, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, and serve as a possible model for waning immunity, showed breakthrough lung infection and pneumonia with B.1.617.2. Thus, as levels of immunity induced by mRNA vaccines decline, breakthrough infection and disease likely will occur with some SARS-CoV-2 variants, suggesting a need for additional booster regimens.

microbiology↗

bioRxiv2021

Multivalent designed proteins protect against SARS-CoV-2 variants of concern

Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC50 values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness. One-Sentence SummaryWe designed, developed, and characterized potent, trivalent miniprotein binders that provide prophylactic and therapeutic protection against emerging SARS-CoV-2 variants of concern.

synthetic biology↗

bioRxiv2021

An intranasal vaccine durably protects against SARS-CoV-2 variants in mice

SARS-CoV-2 variants that attenuate antibody neutralization could jeopardize vaccine efficacy and the end of the COVID-19 pandemic. We recently reported the protective activity of a single-dose intranasally-administered spike protein-based chimpanzee adenovirus-vectored vaccine (ChAd-SARS-CoV-2-S) in animals, which has advanced to human trials. Here, we assessed its durability, dose-response, and cross-protective activity in mice. A single intranasal dose of ChAd-SARS-CoV-2-S induced durably high neutralizing and Fc effector antibody responses in serum and S-specific IgG and IgA secreting long-lived plasma cells in the bone marrow. Protection against a historical SARS-CoV-2 strain was observed across a 100-fold vaccine dose range and over a 200-day period. At 6 weeks or 9 months after vaccination, serum antibodies neutralized SARS-CoV-2 strains with B.1.351 and B.1.1.28 spike proteins and conferred almost complete protection in the upper and lower respiratory tracts after challenge. Thus, in mice, intranasal immunization with ChAd-SARS-CoV-2-S provides durable protection against historical and emerging SARS-CoV-2 strains.

microbiology↗

bioRxiv2021

Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Despite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to rise. Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 receptor binding domain. Here, we investigated the capacity of modified versions of one lead binder, LCB1, to protect against SARS-CoV-2-mediated lung disease in human ACE2-expressing transgenic mice. Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung even when given as many as five days before or two days after virus inoculation. Importantly, LCB1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support development of LCB1v1.3 for prevention or treatment of SARS-CoV-2 infection.

microbiology↗

bioRxiv2019

Impact of peripheral mutations on the access channels of human cytochrome P450 1A2

As an important member of cytochrome P450 (CYP) enzymes, human CYP1A2 is associated with the metabolism of caffeine and melatonin and the activation of precarcinogens. Besides, this CYP protein also involves in metabolizing 5-10% of clinical medicines. Some peripheral mutations in CYP1A2 (P42R, I386F, R431W, and R456H) significantly decrease the enzyme activities, resulting in a vital reduction in substrate metabolisms. To explore the effects of these peripheral mutations, we constructed a membrane-binding model for the full-length human CYP1A2 and studied their dynamic behaviors on lipid membranes. Free energy calculations indicate that the peripheral mutations donot influence substrate binding. P42R is located in the N-terminal anchor, and its positive charged sidechain is adverse to membrane binding. I386F enhances the van der Waals contacts of the water channel bottleneck and R456H breaks the hydrogen bonding interactions that function to position the BC loop, both of which result in a significant inhibition on the water channel. R431W causes a sidechain conformational rearrangement for aromatic residues around the substrate channel, making it in a closed state in most cases. Our computational simulations demonstrate that pi-pi stacking interactions are essential for substrate binding and channel opening. We hope that these findings may be of general relevance to the mutation-induced activity changes for CYP proteins, providing useful information for understanding the CYP-mediated drug metabolism.

biophysics↗

bioRxiv2018

Influence of food and Nosema ceranae infection on the gut microbiota of Apis cerana workers

BackgroundGut microbiota plays an essential role in bees health. To elucidate the effect of food and Nosema ceranae infection on the gut microbiota of honeybee Apis cerana, we used 16S rRNA sequencing to survey the gut microbiota of honeybee workers fed with sugar water or beebread and inoculated with or without N. ceranae.\n\nResultsThe gut microbiota of A. cerana is dominated by Serratia, Snodgrassella, and Lactobacillus genera. The overall gut microbiota diversity was significantly differential by food type. The N. ceranae infection significantly affects the gut microbiota only at bees fed with sugar water. Higher abundance of Lactobacillus, Gluconacetobacter and Snodgrassella and lower abundance of Serratia were found in bees fed with beebread than with sugar water. N. ceranae infection led to higher abundance of Snodgrassella and lower abundance of Serratia in sugar-fed bees. Imputed bacterial KEGG pathways showed the significant metagenomics functional differences by feeding and N. ceranae infections. Furthermore, A. cerana workers fed with sugar water showed lower N. ceranae spore loads but higher mortality than those fed with beebread. The cumulative mortality was strongly positive correlated (rho=0.61) with the changes of overall microbiota dissimilarities by N. ceranae infection.\n\nConclusionsBoth food and N. ceranae infection significantly affect the gut microbiota in A. cerana workers. Beebread feeding not only provide better nutrition but also help establish a more stabled gut microbiota therefore protect bee in response to N. ceranae infection.\n\nAbstract ImportanceGut microbiota plays an essential role in bees health. Scientific evidence suggests the diet and infection can affect the gut microbiota and modulate the gut health, however the interplay between those two factors and bee gut microbiota is not well known. In this study, we used high-throughput sequencing method to monitor the changes of gut microbiota by both food intake and the Nosema ceranae infection. Our result showed that the gut microbiota composition and diversity of Asia Honeybee was significantly associated with both food intake and the N. ceranae infection. More interestingly, bees fed with beebread showed higher microbiota stability and less mortality than those fed with sugar water when infected by N. ceranae. Those data suggest the potential role of beebread, not only providing better nutrition but also helping establish a more stabled gut microbiota to protect bee against N. ceranae infection.

microbiology↗

bioRxiv2018

Rhamnolipids from Pseudomonas aeruginosa disperse the Biofilms of Sulfate-Reducing Bacteria

Biofilm formation is an important problem for many industries. Desulfovibrio vulgaris is the representative sulfate-reducing bacterium (SRB) which causes metal corrosion in oil wells and drilling equipment, and the corrosion is related to its biofilm formation. Biofilms are extremely difficult to remove since the cells are cemented in a polymer matrix. In an effort to eliminate SRB biofilms, we examined the ability of supernatants from Pseudomonas aeruginosa PA14 to disperse SRB biofilms. We found that the P. aeruginosa supernatants dispersed more than 98% of the biofilm. To determine the genetic basis of this SRB biofilm dispersal, we examined a series of P. aeruginosa mutants and found that mutants rhlA, rhlB, rhlI, and rhlR, defective in rhamnolipids production, had significantly reduced levels of SRB biofilm dispersal. Corroborating these results, purified rhamnolipids dispersed SRB biofilms, and rhamnolipids were detected in the P. aeruginosa supernatants. Hence, P. aeruginosa supernatants disperse SRB biofilms via rhamnolipids. In addition, the supernatants of P. aeruginosa dispersed the SRB biofilms more readily than protease in M9 glucose minimum medium and were also effective against biofilms of Escherichia coli and Bacillus subtilis.

microbiology↗