Biology subjects

Niu, X.

Publications and source records attributed to Niu, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Trapping Devices of Carnivorous Fungus Arthrobotrys oligospora Can Isolate Heat-Triggered Excess Irons

Under low-nutrient conditions, Arthrobotrys oligospora and other NTFs can differentiate their mycelia into specialized trapping devices for capturing prey as their nutritional source. Using energy-dispersive X-ray spectroscopy (EDX) in conjunction with transmission electron microscopy (TEM), we identified that the characteristic electron-dense bodies in trapping devices contained more iron than vacuoles and mitochondria. Meanwhile, fungal mycelial cells used effective desferriferrichromes for iron chelation and storage. Complex bioassays showed that electron-dense bodies represent a novel type of microbial iron storage particle and trapping devices in A. oligospora function as an unprecedented phenotypic system for iron storage. Unexpectedly, all NTFs lack a crucial Ccc1-mediated vacuolar iron detoxification mechanism, which is conserved in most fungi. Inserting the Ccc1 gene cloned from yeast into A. oligospora significantly reduced formation of trapping devices and inhibited nematicidal activity. Notably, Bayesian relaxed molecular clock analysis indicated that the loss of Ccc1-mediated vacuolar iron storage occurred during the Late Paleozoic Ice Age, while the origin of the trapping devices and the acquisition of desferriferrichrome biosynthesis were strongly associated with significantly elevated temperatures. Temperature bioassays demonstrated that the formation of trapping devices is highly temperature-dependent, with free iron content in mycelial cells being inversely proportional to temperature, consistent with that A. oligospora is sensitive to high temperatures and fails to grow above 30{degrees}C. Our findings revealed that global temperature fluctuations are a crucial driver of the genetic evolution of NTFs, as a catalyst for the origin of trapping devices, which are a novel phenotypic indicator of eukaryotic iron overload. Author summaryWe found that a unique group of carnivorous fungi has evolved specialized trapping devices to sequester excess iron, compensating for the absence of the crucial Ccc1-mediated vacuolar iron detoxification pathway, which is conserved in most fungi. Furthermore, we report for the first time that elevated temperature is a non-trophic factor that induces iron overload in eukaryotes, as iron content and composition in fungal mycelia are negatively correlated with temperature. Our findings suggest that nematode-trapping fungi could serve as a potential eukaryotic model for investigating the dynamic regulation mechanisms of iron homeostasis, which could contribute to the development of therapies for iron overload-related diseases in humans. In humans, iron overload leads to tissue damage, particularly in the cardiovascular system. It has long been assumed that iron overload occurs when iron intake is increased over an extended period, either through repeated red blood cell transfusions or enhanced absorption from the gastrointestinal tract. Caucasians are particularly susceptible to iron overload and the complications of hemochromatosis due to a higher incidence of mutations in the homeostatic iron regulation gene within this population. The discovery of eukaryotes exhibiting an iron overload phenotype when exposed to heat holds significant implications for developing treatments and strategies for human iron overload disorders.

evolutionary biology↗

bioRxiv2024

Omicron-specific ultra-potent SARS-CoV-2 neutralizing antibodies targeting the N1/N2 loop of Spike N-terminal domain

A multitude of functional mutations continue to emerge on the N-terminal domain (NTD) of the spike protein in SARS-CoV-2 Omicron subvariants. Understanding the immunogenicity of Omicron NTD and the properties of antibodies elicited by it is crucial for comprehending the impact of NTD mutations on viral fitness and guiding vaccine design. In this study, we find that most of NTD-targeting antibodies isolated from individuals with BA.5/BF.7 breakthrough infection (BTI) are ancestral (wildtype or WT)-reactive and non-neutralizing. Surprisingly, we identified five ultra-potent neutralizing antibodies (NAbs) that can only bind to Omicron but not WT NTD. Structural analysis revealed that they bind to a unique epitope on the N1/N2 loop of NTD and interact with the receptor-binding domain (RBD) via the light chain. These Omicron-specific NAbs achieve neutralization through ACE2 competition and blockage of ACE2-mediated S1 shedding. However, BA.2.86 and BA.2.87.1, which carry insertions or deletions on the N1/N2 loop, can evade these antibodies. Together, we provided a detailed map of the NTD-targeting antibody repertoire in the post-Omicron era, demonstrating their vulnerability to NTD mutations enabled by its evolutionary flexibility, despite their potent neutralization. These results highlighted the importance of considering the immunogenicity of NTD in vaccine design. Author SummaryCOVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a major global public health concern four years after its emergence. The N-terminal domain (NTD) is a critical component of the spike glycoprotein, which is pivotal for SARS-CoV-2 cellular entry and serves as a primary target for antibody therapeutics and vaccine development. Characterizing the properties of antibodies elicited by NTD of Omicron sublineages is crucial for understanding viral evolution and guiding vaccine design. Here, we show that Omicron infection after vaccination induces majorly non-neutralizing NTD antibodies. Still, we identified a class of ultra-potent neutralizing antibodies (NAbs) which specifically bind to the NTD of Omicron sublineages. These NAbs neutralize the virus by competing with ACE2 and blocking ACE2-mediated S1 shedding. Structural analyses reveal that these antibodies target a unique epitope on the N1/N2 loop of NTD, and intriguingly interact with the receptor-binding domain (RBD) of spike glycoprotein. This class of NAbs with the special binding pattern, are escaped by BA.2.86 and BA.2.87.1 sublineages, shedding light on the role of recently emerged mutations in the N1/N2 loop of NTD. Our findings provide fresh insights into the immunogenicity of Omicron NTD, highlighting its capacity for antibody evasion due to its evolutionary flexibility. This underscores the importance of carefully considering the NTD component in vaccine design.

immunology↗

bioRxiv2024

Prime editor-based high-throughput screening reveals functional synonymous mutations in the human genome

Synonymous mutations are generally considered neutral, while their roles in the human genome remain largely unexplored. Herein, we employed the PEmax system to create a library of 297,900 epegRNAs and performed extensive screening to identify synonymous mutations that impact cell fitness. While most synonymous mutations are neutral, we found that some can elicit phenotypic effects. By developing a specialized machine learning tool, we uncovered their impact on various biological processes such as mRNA splicing and transcription, supported by multifaceted experimental evidence. Notably, synonymous mutations can alter RNA folding and affect translation, as demonstrated by PLK1_S2. By integrating screening data with our model, we successfully predicted clinically deleterious synonymous mutations. This research deepens our understanding of synonymous mutations and provides insights for clinical disease studies.

genetics↗

bioRxiv2024

Mining the biosynthetic landscape of lactic acid bacteria unearths a new family of RiPPs assembled by a novel type of ThiF-like adenylyltransferases

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are chemically diverse natural products of ribosomal origin. These peptides, which frequently act as signals or antimicrobials, are biosynthesized by conserved enzymatic machineries, making genome mining a powerful strategy for unearthing previously uncharacterized members of their class. Herein, we investigate the untapped biosynthetic potential of Lactobacillales (i.e. lactic acid bacteria) - an order of Gram-positive bacteria closely associated with human life, including pathogenic species and industrially-relevent fermenters of dairy products. Through genome mining methods, we systematically explored the distribution and diversity of ThiF-like adenylyltransferases-utilizing RiPP systems in lactic acid bacteria and identified a number of unprecedented biosynthetic gene clusters. In one of these clusters, we found a previously undescribed group of macrocyclic imide biosynthetic pathways containing multiple transporters and may be involved in potential quorum sensing (QS) system. Through in vitro assays, we determined that one such adenylyltranferase specifically catalyzes the intracyclization of its precursor peptide through macrocyclic imide formation. Incubating the enzyme with various primary amines revealed it could effectively amidate the C-terminus of the precursor peptide. This new transformation adds to the growing list of Natures peptide macrocyclization strategies and expands the impressive catalytic repertoire of the adenylyltransferase family. The diverse RiPP systems identified herein represent a vast, unexploited landscape for discovery of novel class of natural products and potential QS systems. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/593846v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1cd3125org.highwire.dtl.DTLVardef@55a546org.highwire.dtl.DTLVardef@d5a325org.highwire.dtl.DTLVardef@1c9e1f3_HPS_FORMAT_FIGEXP M_FIG C_FIG (For Table of Contents use only)

biochemistry↗

bioRxiv2024

Massively parallel interrogation of human functional variants modulating cancer immunosurveillance

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized clinical cancer treatment, while abnormal PD-L1 or HLA-I expression in patients can significantly impact the therapeutic efficacy. Somatic mutations in cancer cells that modulate these critical immune regulators are closely associated with tumor progression and ICB response. However, a systematic interpretation of cancer immune-related mutations is still lacking. Here, we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible Serine/Threonine/Tyrosine residues across the human genome, which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression. Notably, we revealed functional mutations that co-regulate PD-L1 and HLA-I expression, represented by the clinically relevant mutation SETD2_Y1666, and verified that it can benefit from immunotherapy in vivo. Our findings generate an unprecedented resource of functional residues regulating cancer immunosurveillance, meanwhile, offer valuable guidance for clinical diagnosis, ICB therapy, and the development of innovative drugs in cancer treatment.

cancer biology↗

bioRxiv2024

Yeast poly(A)-binding protein (Pab1) controls translation initiation in vivo primarily by blocking mRNA decapping and decay

Poly(A)-binding protein (Pab1 in yeast) is involved in mRNA decay and translation initiation, but its molecular functions are incompletely understood. We found that auxin-induced degradation of Pab1 reduced bulk mRNA and polysome abundance in a manner suppressed by deleting the catalytic subunit of decapping enzyme (dcp2{Delta}), demonstrating that enhanced decapping/degradation is the major driver of reduced mRNA abundance and protein synthesis at limiting Pab1 levels. An increased median poly(A) tail length conferred by Pab1 depletion was also nullified by dcp2{Delta}, suggesting that mRNA isoforms with shorter tails are preferentially decapped/degraded at limiting Pab1. In contrast to findings on mammalian cells, the translational efficiencies (TEs) of many mRNAs were altered by Pab1 depletion; however, these changes were broadly diminished by dcp2{Delta}, suggesting that reduced mRNA abundance is a major driver of translational reprogramming at limiting Pab1. Thus, assembly of the closed-loop mRNP via PABP-eIF4G interaction appears to be dispensable for normal translation of most yeast mRNAs in vivo. Interestingly, histone mRNAs and proteins are preferentially diminished on Pab1 depletion dependent on Dcp2, accompanied by activation of internal cryptic promoters in the manner expected for reduced nucleosome occupancies, revealing a new layer of post-transcriptional control of histone gene expression.

genomics↗

bioRxiv2024

Humoral immunogenicity comparison of XBB and JN.1 in human infections

The continuous evolution of SARS-CoV-2, particularly the emergence of the BA.2.86/JN.1 lineage replacing XBB lineages, necessitates re-evaluation of current vaccine compositions. Here, we provide a comprehensive analysis of the humoral immune response to XBB and JN.1 human exposures, emphasizing the need for JN.1-lineage-based boosters. We demonstrate the antigenic distinctiveness of XBB and JN.1 lineages in SARS-CoV-2-naive individuals but not in those with prior vaccinations or infections, and JN.1 infection elicits superior plasma neutralization titers against its subvariants. We highlight the strong immune evasion and receptor binding capability of KP.3, supporting its foreseeable prevalence. Extensive analysis of the BCR repertoire, isolating [~]2000 RBD-specific monoclonal antibodies (mAbs) with their targeting epitopes characterized by deep mutational scanning (DMS), underscores the systematic superiority of JN.1-elicited memory B cells (MBCs). Notably, Class 1 IGHV3-53/3-66-derived neutralizing antibodies (NAbs) contribute majorly within wildtype (WT)-reactive NAbs against JN.1. However, KP.2 and KP.3 evade a substantial subset of them, even those induced by JN.1, advocating for booster updates to KP.3 for optimized enrichment. JN.1-induced Omicron-specific antibodies also demonstrate high potency across all Omicron lineages. Escape hotspots of these NAbs have mainly been mutated in Omicron RBD, resulting in higher immune barrier to escape, considering the probable recovery of previously escaped NAbs. Additionally, the prevalence of broadly reactive IGHV3-53/3-66- encoding antibodies and MBCs, and their capability of competing with all Omicron-specific NAbs suggests their inhibitory role on the de novo activation of Omicron-specific naive B cells, potentially explaining the heavy immune imprinting in mRNA-vaccinated individuals. These findings delineate the evolving antibody response to Omicron antigenic shift from XBB to JN.1, and highlight the importance of developing JN.1 lineage, especially KP.3-based vaccine boosters, to enhance humoral immunity against current and future SARS-CoV-2 variants.

immunology↗

bioRxiv2024

A generalized framework to identify SARS-CoV-2 broadly neutralizing antibodies

Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain (RBD) are used to treat and prevent COVID-19. However, the rapid evolution of SARS-CoV-2 drives continuous escape from therapeutic mAbs. Therefore, the ability to identify broadly neutralizing antibodies (bnAbs) against future variants is needed. Here, we use deep mutational scanning (DMS) to predict viral RBD evolution and to select for mAbs neutralizing both existing and prospective variants. A retrospective analysis of 1,103 SARS-CoV-2 wildtype-elicited mAbs shows that this method can increase the probability of identifying effective bnAbs against the XBB.1.5 strain from 1% to 40% in an early pandemic setup. Among these bnAbs, BD55-1205 exhibited potent activity against all tested variants. Cryo-EM structural analyses revealed the receptor mimicry of BD55-1205, explaining its broad reactivity. Delivery of mRNA-LNPs encoding BD55-1205-IgG in mice resulted in ~5,000 serum NT50 against XBB.1.5, HK.3.1, and JN.1 variants. Combining bnAb identification using viral evolution prediction with the versatility of mRNA delivery technology can enable rapid development of next-generation antibody-based countermeasures against SARS-CoV-2 and potentially other pathogens with pandemic potential.

immunology↗

bioRxiv2024

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals. HIGHLIGHTSO_LISerum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle. C_LIO_LIThe mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism. C_LIO_LIAcetylation of the MPC complex modulates mitochondrial pyruvate uptake. C_LIO_LIMPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals. C_LI

neuroscience↗

bioRxiv2024

Antigenicity assessment of SARS-CoV-2 saltation variant BA.2.87.1

The recent emergence of a SARS-CoV-2 saltation variant, BA.2.87.1, which features 65 spike mutations relative to BA.2, has attracted worldwide attention. In this study, we elucidate the antigenic characteristics and immune evasion capability of BA.2.87.1. Our findings reveal that BA.2.87.1 is more susceptible to XBB-induced humoral immunity compared to JN.1. Notably, BA.2.87.1 lacks critical escaping mutations in the receptor binding domain (RBD) thus allowing various classes of neutralizing antibodies (NAbs) that were escaped by XBB or BA.2.86 subvariants to neutralize BA.2.87.1, although the deletions in the N-terminal domain (NTD), specifically 15-23del and 136-146del, compensate for the resistance to humoral immunity. Interestingly, several neutralizing antibody drugs have been found to restore their efficacy against BA.2.87.1, including SA58, REGN-10933 and COV2-2196. Hence, our results suggest that BA.2.87.1 may not become widespread until it acquires multiple RBD mutations to achieve sufficient immune evasion comparable to that of JN.1.

immunology↗

bioRxiv2024

FoxO factors are essential for maintaining organ homeostasis by acting as stress sensors in airway epithelial cells

Airway epithelia must maintain functional and structural homeostasis despite exposure to diverse environmental stressors. FoxO transcription factors are well suited to this task, acting as integration hubs that translate extrinsic and intrinsic signals into appropriate physiological responses. We show that FoxO factors in Drosophila, mouse, and human airway epithelial cells (AECs) undergo nuclear translocation in response to stressors including hypoxia, temperature, and oxidative stress. In human airway epithelial cell lines, individual hFOXO factors show distinct, cell-type-specific activation patterns. In Drosophila, hypoxia was the only stressor among those tested that triggered a dfoxo-dependent innate immune response. Because Drosophila possesses a single FoxO ortholog, loss-of-function analysis directly demonstrated that dfoxo is required for stress resistance in the airway epithelium. Reduced FoxO expression was similarly observed in mouse models of asthma and in airway samples from asthma patients, paralleling the increased stress sensitivity seen upon FoxO loss in flies. While our data do not establish that reduced FOXO levels cause asthma, they indicate that FoxO-dependent stress pathways are altered in diseased airways across species. Together, these findings support a model in which FoxO coordinates adaptive epithelial stress responses that maintain airway homeostasis under environmental challenge.

physiology↗

bioRxiv2023

CRISPRmap: Sequencing-free optical pooled screens mapping multi-omic phenotypes in cells and tissue

Pooled genetic screens are powerful tools to study gene function in a high-throughput manner. Typically, sequencing-based screens require cell lysis, which limits the examination of critical phenotypes such as cell morphology, protein subcellular localization, and cell-cell/tissue interactions. In contrast, emerging optical pooled screening methods enable the investigation of these spatial phenotypes in response to targeted CRISPR perturbations. In this study, we report a multi-omic optical pooled CRISPR screening method, which we have named CRISPRmap. Our method combines a novel in situ CRISPR guide identifying barcode readout approach with concurrent multiplexed immunofluorescence and in situ RNA detection. CRISPRmap barcodes are detected and read out through combinatorial hybridization of DNA oligos, enhancing barcode detection efficiency, while reducing both dependency on third party proprietary sequencing reagents and assay cost. Notably, we conducted a multi-omic base-editing screen in a breast cancer cell line on core DNA damage repair genes involved in the homologous recombination and Fanconi anemia pathways investigating how nucleotide variants in those genes influence DNA damage signaling and cell cycle regulation following treatment with ionizing radiation or DNA damaging agents commonly used for cancer therapy. Approximately a million cells were profiled with our multi-omic approach, providing a comprehensive phenotypic assessment of the functional consequences of the studied variants. CRISPRmap enabled us to pinpoint likely-pathogenic patient-derived mutations that were previously classified as variants of unknown clinical significance. Furthermore, our approach effectively distinguished barcodes of a pooled library in tumor tissue, and we coupled it with cell-type and molecular phenotyping by cyclic immunofluorescence. Multi-omic spatial analysis of how CRISPR-perturbed cells respond to various environmental cues in the tissue context offers the potential to significantly expand our understanding of tissue biology in both health and disease.

genomics↗

bioRxiv2023

Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure

While the BA.2.86 variant demonstrated significant antigenic drift and enhanced ACE2 binding affinity, its ability to evade humoral immunity was relatively moderate compared to dominant strains like EG.5 and HK.3. However, the emergence of a new subvariant, JN.1 (BA.2.86.1.1), which possesses an additional spike mutation, L455S, compared to BA.2.86, showed a markedly increased prevalence in Europe and North America, especially in France. Here, we found that L455S of JN.1 significantly enhances immune evasion capabilities at the expense of reduced ACE2 binding affinity. This mutation enables JN.1 to effectively evade Class 1 neutralizing antibodies, offsetting BA.2.86s susceptibility and thus allowing it to outcompete both its precursor BA.2.86 and the prevailing variants HV.1 (XBB.1.5+L452R+F456L) and JD.1.1 (XBB.1.5+L455F+F456L+A475V) in terms of humoral immune evasion. The rapid evolution from BA.2.86 to JN.1, similar to the earlier transition from BA.2.75 to CH.1.1, highlights the importance of closely monitoring strains with high ACE2 binding affinity and distinct antigenicity, despite their temporarily unremarkable immune evasion capabilities. Such strains could survive and transmit at low levels, since their large antigenic distance to dominant strains allow them to target distinct populations and accumulate immune-evasive mutations rapidly, often at the cost of receptor binding affinity.

immunology↗

bioRxiv2023

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

cancer biology↗

bioRxiv2023

Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein driving the genesis of Omicron variants

Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population immunity and genesis of virus variants has long been suggested but its molecular basis remains poorly understood. Here, we identify a class of SARS-CoV-2 neutralising public antibodies defined by their shared usage of VL6-57 light chains. Although heavy chains of diverse genotypes are utilized, convergent HCDR3 rearrangements have been observed among these public antibodies to cooperate with germline VL6-57 LCDRs to target a convergent epitope defined by RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this class of VL6-57 antibodies is present in SARS-CoV-2-naive individuals and is clonally expanded in most COVID-19 patients. We confirm that Omicron specific substitutions at S371, S373 and S375 mediate escape of antibodies of the VL6-57 class. These findings support that this class of public antibodies constitutes immune pressure promoting the introduction of S371L/F-S373P-S375F in Omicron variants. The results provide further molecular evidences to support that antigenic evolution of SARS-CoV-2 is driven by antibody mediated population immunity.

biochemistry↗

bioRxiv2023

Antigenicity and infectivity characterization of SARS-CoV-2 BA.2.86

The recently identified SARS-CoV-2 variant, BA.2.86, which carries a substantial number of Spike mutations, has raised a global alarm. An immediate assessment of its antigenic properties and infectivity is necessary. Here, we reveal the distinct antigenicity of BA.2.86 compared with previous variants including XBB.1.5. BA.2.86 significantly evades convalescent plasma from XBB breakthrough infection (BTI) and reinfections. Key mutations that mediate the enhanced resistance include N450D, K356T, L452W, A484K, V483del, and V445H on the RBD, while BA.2.86s NTD mutations and E554K on SD1 also largely contribute. However, we found that BA.2.86 pseudovirus exhibits compromised efficiency of infecting HEK293T-hACE2 cells compared to XBB.1.5 and EG.5, which may be caused by K356T, V483del, and E554K, and could potentially limit BA.2.86s transmissibility. In sum, it appears that BA.2.86 has traded its infectivity for higher immune evasion during long-term host-viral evolution. Close attention should be paid to monitoring additional mutations that could improve BA.2.86s infectivity.

immunology↗

bioRxiv2023

Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455-456 enhances antibody evasion and ACE2 binding

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of XBB lineages on the receptor-binding domain (RBD) L455F and F456L is observed, resulting in variants like EG.5, FL.1.5.1, XBB.1.5.70, and HK.3. Here, we show that neutralizing antibody (NAb) evasion drives the convergent evolution of F456L, while the epistatic shift caused by F456L enables the subsequent convergence of L455F through ACE2 binding enhancement and further immune evasion. L455F and F456L evade Class 1 NAbs, reducing the neutralization efficacy of XBB breakthrough infection (BTI) and reinfection convalescent plasma. Importantly, L455F single substitution significantly dampens receptor binding; however, the combination of L455F and F456L forms an adjacent residue flipping, which leads to enhanced NAbs resistance and ACE2 binding affinity. The perturbed receptor-binding mode leads to the exceptional ACE2 binding and NAb evasion, as revealed by structural analyses. Our results indicate the evolution flexibility contributed by epistasis cannot be underestimated, and the evolution potential of SARS-CoV-2 RBD remains high.

immunology↗

bioRxiv2023

Large-scale population genomics of Malayan pangolins reveals deep diversification and a new species

BackgroundArchipelagos and oceanic islands often present high percentage of endemism due to rapid speciation. The Malayan pangolin is a species distributing at both mainland (southern Yunnan, China) and oceanic islands via Malayan peninsula, which may result in deep differentiation among populations. In-depth investigation of population structure and genetic consequences for such species is of vital importance for their protection and conservation, practically for the critically endangered Malayan pangolin that is suffering from poaching, illegal trade, and habitat loss. ResultsHere we carried out a large-scale population genomic analysis for Malayan pangolins, and revealed three highly distinct genetic populations in this species, two of which are now being reported for the first time. Based on multiple lines of genomic and morphological evidence, we postulate the existence of a new pangolin species (Manis_1). Genetic diversity and recent inbreeding were both at a moderate level for both Malayan pangolins and Manis_1, but mainland Malayan pangolins presented relatively lower genetic diversity, higher inbreeding and fitness cost than island populations. ConclusionsWe found extremely deep and graded differentiation in Malayan pangolins, with two newly discovered genetic populations and a new pangolin species that is closely related to the Philippine pangolin than the typical Malayan pangolin, but a distant relative of the Indian pangolin. Anthropogenic factors did not significantly weaken the basis of genetic sustainability for Malayan pangolins, but mainland Malayan pangolins should be paid more attention for conservation due to higher genetic risks than island populations.

genomics↗