Biology subjects

Guo, H.

Publications and source records attributed to Guo, H..

At least 163 records · Page 9Linked to original sources

bioRxiv2021

Gram-positive bacteria secrete RNA aptamers to activate human STING for IL-1β release.

Molecular mechanisms through which Gram-positive bacteria induce the canonical inflammasome are poorly understood. Here, we studied the effects of Group B streptococci (GBS) and Staphylococcus aureus (SA) on inflammasome activation in human macrophages. Dinucleotide binding small RNA aptamers released by SA and GBS were shown to trigger increased IL-1{beta} generation by inflammasomes. The stimulator of interferon genes-STING as a central mediator of innate immune responses has been identified as the key target of pathogenic RNA. Multi-lamellar lipid bodies (MLBs) produced by SA function as vehicles for the RNA aptamers. Notably, expression of RNA aptamers is controlled by an accessory gene regulator quorum sensing system of the bacteria. These findings have been translated to patients with Gram-positive sepsis showing hallmarks of MLB-RNA-mediated inflammasome activation. Together our findings may provide a new perspective for the pathogenicity of Gram-positive bacterial infection in man.

immunology↗

bioRxiv2021

The gravitation-driven stress-reduced urothelial barrier in toad bladder urothelium

The urinary bladder urothelial are highly specialized epithelia that protect the underlying tissues from mechanical stress and seal them from the overlying fluid space. To better understand the maintaining permeability induced electrical potential roles played by urothelial in the bladder, we established a protocol of gravitation stress in toad urothelial, observed the transmembrane potential difference variation. MethodThe toad urothelial were mounted in a using chamber which the chamber was separated to two solution spaces, and stable with 0.9% saline solution. The electrodes were settled on the surface of each side of the preparation, serosal side definite as cathode. The using chamber was settled in the centrifugal rotor and under 300 rpm rotation to obtain a vertically +4G gravitation on serosal chamber 5min. Resulta transient transmembrane potential difference increasing was observed after adding CaCl2 (3% solution) in serosal chamber. The amplitude increasing phase included a rapid and a slowly ascending phase. In gravitation stressed urothelial preparation, CaCl2 induced transient phase was significantly increased, furthermore the secondary slowly ascending phase was much more amplified on its amplitude axis and significantly prolonged on the time scale than that evoked in control preparations. The evoked total amplitude increasing were 10 times higher than that in control. ConclusionThe urinary bladder epithelial layer has a structure which regulates ion permeability as a barrier. The tight junction plays an important role as the intercellular coupling in the apical side of the epithelial cell. On the other hand, it is known that the ion channel exists on the epithelial cell membrane and regulates the physiological process. The gravitation stress weakened the tight junction. The transmembrane potential difference was enhanced both on its amplitude and prolonged time. The gravitation stress induced hyperpolarization that evoked by CaCl2 is one kind of Cl- transfer from serosal chamber in which high Ca2+ in the urothelial basal membrane activated the calcium-activated chloride channels. This outwardly rectifying chloride channel induced hyperpolarization can be blocked by Nppb.

physiology↗

bioRxiv2021

Quantifying concordant genetic effects of de novo mutations on multiple disorders

Exome sequencing on tens of thousands of parent-proband trios has identified numerous deleterious de novo mutations (DNMs) and implicated risk genes for many disorders. Recent studies have suggested shared genes and pathways are enriched for DNMs across multiple disorders. However, existing analytic strategies only focus on genes that reach statistical significance for multiple disorders and require large trio samples in each study. As a result, these methods are not able to characterize the full landscape of genetic sharing due to polygenicity and incomplete penetrance. In this work, we introduce EncoreDNM, a novel statistical framework to quantify shared genetic effects between two disorders characterized by concordant enrichment of DNMs in the exome. EncoreDNM makes use of exome-wide, summary-level DNM data, including genes that do not reach statistical significance in single-disorder analysis, to evaluate the overall and annotation-partitioned genetic sharing between two disorders. Applying EncoreDNM to DNM data of nine disorders, we identified abundant pairwise enrichment correlations, especially in genes intolerant to pathogenic mutations and genes highly expressed in fetal tissues. These results suggest that EncoreDNM improves current analytic approaches and may have broad applications in DNM studies.

genetics↗

bioRxiv2021

A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence define the mechanism of action of apoptolidin family glycomacrolides and establish a path to address OXPHOS-dependent cancers.

biochemistry↗

bioRxiv2021

Identification of a novel lineage bat SARS-related coronaviruses that use bat ACE2 receptor

Severe respiratory disease coronavirus-2 (SARS-CoV-2) causes the most devastating disease, COVID-19, of the recent century. One of the unsolved scientific questions around SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor the highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). Here, we report the identification of a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities to SARS-CoV-2 in the conserved ORF1b region, but only show less than 77.6% to all known SARSr-CoVs in genome level, thus forms a distinct lineage in the Sarbecovirus phylogenetic tree. We then found that RaTG15 receptor binding domain (RBD) can bind to and use Rhinolophus affinis bat ACE2 (RaACE2) but not human ACE2 as entry receptor, although which contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we show that none of the known viruses in bat SARSr-CoV-2 lineage or the novel lineage discovered so far use human ACE2 efficiently compared to SARSr-CoV-2 from pangolin or some of the SARSr-CoV-1 lineage viruses. Collectively, we suggest more systematic and longitudinal work in bats to prevent future spillover events caused by SARSr-CoVs or to better understand the origin of SARS-CoV-2.

microbiology↗

bioRxiv2021

A novel cholinergic neural pathway and its role in the drug relapse

The lateral parabrachial nucleus (LPB) is critical hub implicated in the control of food intake, reward and aversion. Here, we identified a novel cholinergic projection from choline acetyltransferase (ChAT)-positive neurons in external portion of the lateral parabrachial nucleus (eLPBChAT) to {gamma}-aminobutyric acid (GABA) neurons in central nucleus of amygdala (CeAGABA), activation of which could block methamphetamine (METH)-primed conditioned place preference (CPP) in mice.

neuroscience↗

bioRxiv2021

A broadly active fucosyltransferase LmjFUT1 whose mitochondrial localization and catalytic activity is essential in parasitic Leishmania major

Glycoconjugates play major roles in the infectious cycle of the trypanosomatid parasite Leishmania. While GDP-Fucose synthesis is essential (Guo et al 2017), fucosylated glycoconjugates have not been reported in Leishmania major. Four predicted fucosyltransferases appear conventionally targeted to the secretory pathway; SCA1/2 play a role in side-chain modifications of lipophosphoglycan, while gene deletion studies here showed that FUT2 and SCAL were not essential. Unlike most eukaryotic glycosyltransferases, the predicted 1-2 fucosyltransferase encoded by FUT1 localized to the mitochondrion. A quantitative plasmid segregation assay, expressing FUT1 from the multicopy episomal pXNG vector in a chromosomal null {Delta}fut1- background, established that FUT1 is essential. Similarly "plasmid shuffling" confirmed that both enzymatic activity and mitochondrial localization were required for viability, comparing import-blocked or catalytically inactive enzymes respectively. Enzymatic assays of tagged proteins expressed in vivo or of purified recombinant FUT1 showed it had a broad fucosyltransferase activity including glycan and peptide substrates. Unexpectedly a single rare {Delta}fut1-s segregant ({Delta}fut1s) was obtained in rich media, which showed severe growth defects accompanied by mitochondrial dysfunction and loss, all of which were restored upon FUT1 re-expression. Thus, FUT1 along with the similar Trypanosoma brucei enzyme TbFUT1 (Bandini et al 2021) joins the eukaryotic O-GlcNAc transferase isoform as one of the few glycosyltransferases acting within the mitochondrion. Trypanosomatid mitochondrial FUT1s may offer a facile system for probing mitochondrial glycosylation in a simple setting and their essentiality renders it an attractive target for chemotherapy of these serious human pathogens. Significance StatementAbundant surface glycoconjugates play key roles in the infectious cycle of protozoan parasites including Leishmania. Through defining biosynthetic pathways we identified a fucosyltransferase FUT1 that was localized to the parasite mitochondrion, an atypical compartment for glycosyltransferases. FUT1 was essential for normal growth, requiring both mitochondrial localization and enzymatic activity. Loss of FUT1 in a unique segregant showed extensive mitochondrial defects. Enzymatic tests showed FUT1 could fucosylate glycan and peptide substrates in vitro, although as yet the native substrate is unknown. Trypanosomatid mitochondrial FUT1s may offer a facile system in the future for probing mitochondrial glycosylation in a setting uncomplicated by multiple isoforms targeted to diverse compartments, and its essentiality renders it an attractive target for chemotherapy of these deadly parasites.

microbiology↗

bioRxiv2021

Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

immunology↗

bioRxiv2021

RhizoVision Explorer: Open-source software for root image analysis and measurement standardization

Roots are central to the function of natural and agricultural ecosystems by driving plant acquisition of soil resources and influencing the carbon cycle. Root characteristics like length, diameter, and volume are critical to measure to understand plant and soil functions. RhizoVision Explorer is an open-source software designed to enable researchers interested in roots by providing an easy-to-use interface, fast image processing, and reliable measurements. The default broken roots mode is intended for roots sampled from pots or soil cores, washed, and typically scanned on a flatbed scanner, and provides measurements like length, diameter, and volume. The optional whole root mode for complete root systems or root crowns provides additional measurements such as angles, root depth, and convex hull. Both modes support providing measurements grouped by defined diameter ranges, the inclusion of multiple regions of interest, and batch analysis. RhizoVision Explorer was successfully validated against ground truth data using a novel copper wire image set. In comparison, the current reference software, the commercial WinRhizo, drastically underestimated volume when wires of different diameters were in the same image. Additionally, measurements were compared with WinRhizo and IJ_Rhizo using a simulated root image set, showing general agreement in software measurements, except for root volume. Finally, scanned root image sets acquired in different labs for the crop, herbaceous, and tree species were used to compare results from RhizoVision Explorer with WinRhizo. The two software showed general agreement, except that WinRhizo substantially underestimated root volume relative to RhizoVision Explorer. In the current context of rapidly growing interest in root science, RhizoVision Explorer intends to become a reference software, improve the overall accuracy and replicability of root trait measurements, and provide a foundation for collaborative improvement and reliable access to all. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

plant biology↗

bioRxiv2021

Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 64.3% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development.

immunology↗

bioRxiv2021

Mechanical bistability enabled by ectodermal compression facilitates Drosophila mesoderm invagination

Apical constriction driven by non-muscle myosin II ("myosin") provides a well-conserved mechanism to mediate epithelial folding. It remains unclear how contractile forces near the apical surface of a cell sheet drive out-of-the-plane bending of the sheet and whether myosin contractility is required throughout folding. By optogenetic-mediated acute inhibition of myosin, we find that during Drosophila mesoderm invagination, myosin contractility is critical to prevent tissue relaxation during the early, "priming" stage of folding but is dispensable for the actual folding step after the tissue passes through a stereotyped transitional configuration. The binary response suggests that the mesoderm is mechanically bistable during gastrulation. Combined modeling analysis and experimental measurements suggest that the observed mechanical bistability may arise from apicobasal shrinkage of the surrounding ectoderm, which promotes mesoderm invagination by facilitating a buckling transition. Our results suggest that Drosophila mesoderm invagination requires a joint action of local myosin contractility and mechanical bistability of the epithelium to trigger epithelial buckling.

developmental biology↗

bioRxiv2021

Interactions among rooting traits for deep water and nitrogen uptake in upland and lowland ecotypes of switchgrass (Panicum virgatum L.)

Plant phenotypic plasticity in response to nutrient and water availability is an important adaptation for abiotic stress tolerance. Roots intercept water and nutrients while foraging through soil searching for further resources. Substantial amounts of nitrate can leach into groundwater; yet, little is known about how deep rooting affects this process. Here, we phenotyped root system traits and deep 15N nitrate capture across 1.5 m profiles of solid-media using tall mesocosms in switchgrass (Panicum virgatum L.), a cellulosic bioenergy feedstock. Root and shoot biomass, photosynthesis and respiration, and nutrient uptake traits were quantified in response to a water and nitrate stress factorial experiment in the greenhouse for switchgrass upland (VS16) and lowland (AP13) ecotypes. The two switchgrass ecotypes shared common plastic abiotic responses to nitrogen (N) and water availability and yet showed genotypic differences for root and shoot traits. A significant interaction between nitrogen and water stress for axial and lateral root traits represents a complex and shared root development strategy for stress mitigation. Deep root growth and 15N capture were found to be closely linked to aboveground growth. Together, these results represent the wide genetic pool of switchgrass and that deep rooting promotes nitrate capture, plant productivity, and sustainability. HighlightTwo main ecotypes of switchgrass have both shared and different root responses to varying water and nitrogen conditions, with deep rooting shown to be closely linked to aboveground growth.

plant biology↗

bioRxiv2021

Interplay between brassinosteroids and TORC signaling in Arabidopsis revealed by integrated multi-dimensional analysis

Brassinosteroids (BR) and Target of Rapamycin Complex (TORC) are two major processes coordinating plant growth and stress responses. BRs function through a signaling pathway to extensively regulate gene expression and TORC is known to regulate translation and autophagy. Recent studies revealed that these two pathways crosstalk, but a system-wide view of their interplay is still missing. Thus, we performed transcriptome, proteome, and phosphoproteome profiling of Arabidopsis mutants with altered levels of either BIN2 or RAPTOR1B, two key players in BR and TORC signaling, respectively. We found that perturbation of BIN2 or RAPTOR1B levels affects a common set of gene-products involved in growth and stress responses. Additionally, we performed Multiplexed Assay for Kinase Specificity (MAKS), which provided a system-wide view of direct BIN2 substrates. Furthermore, phosphoproteomic data was used to reconstruct a kinase-signaling network and to identify novel proteins dependent on BR and/or TORC signaling pathways. Loss of function mutants of many of these proteins led to an altered BR response and/or modulated autophagy activity. Altogether, these results provide genome-wide evidence for crosstalk between BR and TORC signaling and established a kinase signaling network that defines the molecular mechanisms of BR and TORC interactions in the regulation of plant growth/stress balance.

plant biology↗

bioRxiv2021

A human antibody with blocking activity to RBD proteins of multiple SARS-CoV-2 variants including B.1.351 showed potent prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus macaques

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein for infection. After the virus sequence was published, we identified two potent antibodies against SARS-CoV-2 RBD from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a phase I clinical trial, showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.

microbiology↗

bioRxiv2021

PEBP regulates balance between apoptosis and autophagy, enabling coexistence of arbovirus and insect vector

Apoptosis and autophagy are two most prominent forms of programmed cell deaths (PCD) that have been implicated in antiviral immunity in vertebrate and plant hosts. Arboviruses are able to coexist with its arthropod vectors by coordinating the PCD immunity, but the regulatory mechanism involved is largely unknown. We found that the coat protein (CP) of an insect-borne plant virus TYLCV directly interacted with a phosphatidylethanolamine-binding protein (PEBP) of its insect vector whitefly to negatively influence the MAPK signaling cascade. As a result, the apoptosis was activated in whitefly which increased viral loading. Simultaneously, the PEBP4-CP interaction liberated ATG8, the hallmark of autophagy initiation, and eliminates arbovirus. Furthermore, apoptosis-promoted virus loading was compromised by agonist-induced autophagy, but autophagy-associated suppression on virus loading was unaffected by apoptosis agonist or inhibitor, suggesting that virus loading was predominantly determined by autophagy rather than by apoptosis. Our results demonstrated that maintaining a mild immune response by coordinating apoptosis and autophagy processes presumably could facilitate coexistence of the arbovirus and its insect vector. Taken together, immune homeostasis shaped by two types of PCD may facilitate the arbovirus preservation within the insect vector. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/427364v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@a1e3baorg.highwire.dtl.DTLVardef@6ddc26org.highwire.dtl.DTLVardef@906b04org.highwire.dtl.DTLVardef@161db14_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIInteraction between whitefly PEBP4 and TYLCV CP suppresses phosphorylation of MAPK cascade, activating apoptosis C_LIO_LITYLCV CP liberates PEBP4-bound ATG8, resulting in lipidation of ATG8 and initiation of autophagy. C_LIO_LIPEBP4 balances apoptosis and autophagy in viruliferous whitefly to optimize virus loading without obvious fitness cost. C_LI

microbiology↗

bioRxiv2021

Natural variations in the P-type ATPase heavy metal transporter ZmCd1 controlling cadmium accumulation in maize grains

Cadmium (Cd) accumulation in maize grains is detrimental to human health. Developing maize varieties with low-Cd contents via marker-assisted selection is important for ensuring the production of maize grains safe for consumption. However, the key gene controlling maize grain Cd accumulation has not been cloned. In this study, we identified two major loci for maize grain Cd accumulation (qCd1 and qCd2) on chromosome 2 during a genome-wide association study (GWAS). The qCd1 locus was analyzed by bulked segregant RNA-seq and fine mapping with a biparental segregating population of Jing724 (low-Cd line) and Mo17 (high-Cd line). The ZmCd1 candidate gene in the qCd1 locus encodes a vacuolar membrane-localized heavy metal P-type ATPase transporter, ZmHMA3, which is orthologous to the tonoplast Cd transporter OsHMA3. Genomic DNA sequence and transcript analyses suggested that a transposon in intron 1 of ZmCd1 is responsible for the abnormal amino acid sequence in Mo17. An EMS mutant analysis and an allelism test confirmed ZmCd1 influences maize grain Cd accumulation. The natural variations in ZmCd1 were used to develop four PCR-based molecular markers, which revealed five ZmCd1 haplotypes in the GWAS population. The molecular markers were also used to predict the grain Cd contents in commonly cultivated maize germplasms in China. The predicted Cd contents for 36 inbred lines and 13 hybrids were consistent with the measured Cd contents. Furthermore, several low-Cd elite inbred lines and hybrids were identified, including Jing2416, MC01, Jingnonke728, and Jingke968. Therefore, the molecular markers developed in this study are applicable for molecular breeding and developing maize varieties with low grain Cd contents.

plant biology↗

bioRxiv2021

iRGD-liposomes enhance tumor delivery and therapeutic efficacy of antisense oligonucleotide drugs against primary prostate cancer and bone metastasis

Nucleotide-based drugs, such as antisense oligonucleotides (ASOs), have unique advantages in treating human diseases as they provide virtually unlimited ability to target any gene. However, their clinical translation faces many challenges, one of which is poor delivery to the target tissue in vivo. This problem is particularly evident in solid tumors. Here, we functionalized liposomes with a tumor-homing and -penetrating peptide, iRGD, as a carrier of an ASO against androgen receptor (AR) for prostate cancer treatment. The iRGD-liposomes exhibited a high loading efficiency of AR-ASO, and an efficient knockdown of AR gene products was achieved in vitro, including AR splice variants. In vivo, iRGD-liposomes significantly increased AR-ASO accumulation in the tumor tissue and decreased AR expression relative to free ASOs in prostate tumors established as subcutaneous xenografts. Similar results were obtained with intra-tibial xenografts modeling metastasis to bones, the predominant site of metastasis for prostate cancer. In treatment studies, iRGD-liposomes markedly improved the AR-ASO efficacy in suppressing the growth of both subcutaneous xenografts and intra-tibial xenografts. The inhibitory effect on tumor growth was also significantly prolonged by the delivery of the AR-ASO in the iRGD-liposomes. Meanwhile, iRGD-liposomes did not increase ASO accumulation or toxicity in healthy organs. Overall, we provide here a delivery system that can significantly increase ASO accumulation and efficacy in solid tumors. These benefits are achieved without significant side effects, providing a way to increase the antitumor efficacy of ASOs.

cancer biology↗

bioRxiv2021

Structural and molecular basis for foot-and-mouth disease virus neutralization by two potent protective antibodies

Outbreaks of Foot-and-mouth disease (FMD) caused by FMD virus result in significant economic losses. Vaccination is helpful, but the benefits are diminished with antigenic diversity within serotypes, instability of the immunogen and inability to confer protection for long durations. Here we have further dissected the mechanisms underpinning the protective efficacy of two previously reported neutralizing antibodies (NAbs), M8 and M170. The atomic details of the epitopes of M8 and M170 unveiled suggest that protection is conferred by disrupting the virus-receptor interactions. Consequently, administration of these NAbs conferred prophylactic and therapeutic benefit in guinea pigs, raising the possibility of administering NAbs before or during vaccination to confer immediate protection; well before the bolstering of the immune response by the vaccine. Differences in the residues and the conformation of elements making up the epitopes explain the differences in specificities of M8 and M170. An ability to bind 146S viral particles specifically, but not 12S degraded components, highlights a likely role for M170 in the quality control of vaccines.

biophysics↗