Biology subjects

Xu, S.

Publications and source records attributed to Xu, S..

At least 163 records · Page 9Linked to original sources

bioRxiv2025

Epidermal Cell Dynamics Regulates Rice Lamina Joint Morphogenesis and Leaf Angle Formation through OsZHD1 and OsZHD2 Regulation

The lamina joint is a critical determinant of leaf angle and crop architecture. While epidermal cells play a fundamental role in organ morphogenesis, influencing the overall shape and function of plants, their impact on lamina joint morphology has been largely overlooked. Here, we tracked the cellular dynamics of the rice lamina joint epidermis during leaf angle formation. We found that the asymmetric elongation between the lateral and medial edges, determined by spatial differences in the longitudinal elongation and number of epidermal cells, was a key factor in leaf angle formation. Mutations in the homeobox genes OsZHD1 and OsZHD2 disrupted the growth patterns of epidermal cells in the lamina joint, resulting in a decreased leaf angle. Restoring OsZHD1 expression in the epidermis reverted the reduced leaf angle phenotype of oszhd1 oszhd2, highlighting the importance of epidermis development for lamina joint morphogenesis. Transcriptome data suggested that OsZHD1 and OsZHD2 were involved in auxin synthesis, which modulates leaf angle by inhibiting the growth of lamina joint epidermal cells. This study underscores the significance of epidermal cells in shaping the lamina joint and elucidates the critical role of OsZHD1 and OsZHD2 in regulating epidermal cell behavior and leaf angle formation.

plant biology↗

bioRxiv2025

Bulk segregant analysis reveals genomic regions associated with imidacloprid resistance in the Colorado potato beetle

Given the increased accessibility of genomic techniques, the speed of evolution of resistance, and the large number of genes involved in resistance, investigations into the genetic basis of resistance in more species are pertinent. Despite being an important agricultural pest, only a limited number of genetic mapping studies based on crossed populations have been performed to identify genes involved in resistance in the Colorado potato beetle (Leptinotarsa decemlineata, CPB). Here, we performed bulk segregant analysis on a mapping population generated by creating advanced intercross lines from five European strains of CPB. We identified eight peaks across chromosomes 1,8,10, and 16 involved in resistance against the neonicotinoid, imidacloprid. We identified 337 genes within these peaks and shortlisted three candidates based on gene expression and functional annotation. Among the three candidates thus identified, we found that an ABC transporter and a galactosyl transferase are expressed in relatively higher amounts in a relatively more susceptible strain than in a resistant strain. We attempted to validate the role of these two genes in insecticide resistance by knocking them down in a resistant strain using RNA interference (RNAi) and performing toxicity experiments. Surprisingly, our results showed that the activation of RNAi machinery reduced imidacloprid resistance and the effect is not specific to the tested candidate genes, which raised a concern on the suitability of using RNAi for validating insecticide resistance mechanisms in CPB.

genetics↗

bioRxiv2025

Transfer learning applied in predicting small molecule bioactivity

Despite over a half-century of effort by computational chemists, developing accurate empirical QSAR (Quantitative Structure-Activity Relationships) models for predicting bioactivity directly from chemical structure has remained elusive. The difficulties have been especially pronounced for virtual screening, finding new active compounds substantially different from the known chemical matter used to train the models. Recent breakthroughs have been achieved by employing transfer of learning across huge numbers of bioactivity assays, greatly increasing the amount and diversity of chemical and biological information that informs each model. An early example was Profile-QSAR (pQSAR), a 2-level stacked model, where level-2 PLS (Partial Least Squares) models characterize compounds by their profile of bioactivity predictions from individual level-1 random forest regression QSAR models built on up to 10,000+ other assays. This study introduces metaNN, a meta-learner that trains deep neural networks (DNN) for each individual assay initialised from a well-generalized consensus DNN optimized across all assays. Comparison of the results suggested that while Profile-QSAR and metaNN perform similarly overall, metaNN works slightly better for smaller assays which were well-predicted by the consensus DNN; whereas pQSAR struggled more with smaller assays, due to the large number of level-1 models but was less sensitive to similarity to an overall consensus. An ensemble average of both methods combined the strengths of each, working better than either alone. The similar performance of the 2 largely orthogonal algorithms raises questions about whether we are approaching a limit of prediction accuracy in transfer learning, for this application scenario.

bioinformatics↗

bioRxiv2024

Identification of QTL-by-Environment Interaction by Controlling Polygenic Background Effect

The QTL by environment interaction (QxE) effect is hard to detect because there are no effective ways to control the genomic background. In this study, we propose a novel linear mixed model that simultaneously analyzes data from multiple environments to detect QxE interactions. This model incorporates two different kinship matrices derived from the genome-wide markers to control both main and interaction polygenic background effects. Simulation studies demonstrated that our approach was more powerful than the meta-analysis and inclusive composite interval mapping methods. We further analyzed four agronomic traits of rice across four environments. A main effect QTL was identified for 1000-grain weight (KGW), while no QTLs were found for tiller number. Additionally, a large QTL with a significant QxE interaction was detected on chromosome 7 affecting grain number, yield and KGW. This region harbored two important genes, PROG1 and Ghd7. Furthermore, we applied our mixed model to analyze lodging in barley across six environments. The six regions exhibiting QxE interaction effects identified by our approach overlapped with the SNPs previously identified using EM and MCMC-based Bayesian methods, further validating the robustness of our approach. Both simulation studies and empirical data analyses showed that our method outperformed all other methods compared.

genetics↗

bioRxiv2024

Integrative Omics reveals genetic basis and TaMYB7-A1's function in wheat WUE and drought resilience

Improving water use efficiency (WUE) and drought resistance in wheat is critical for ensuring global food security under changing climate conditions. Here, we integrated multi-omic data, including population-scale phenotyping, transcriptomics, and genomics, to dissect the genetic and molecular mechanisms underlying WUE and drought resilience in wheat. Genome-wide association studies (GWAS) revealed 8,135 SNPs associated with WUE-related traits, identifying 258 conditional and non-conditional QTLs, many of which co-localized with known drought-resistance genes. Pan-transcriptome analysis uncovered tissue-specific expression patterns, core and unique gene functions, and dynamic sub-genomic biases in response to drought. eQTL mapping pinpointed 146,966 regulatory loci, including condition-specific hotspots enriched for genes involved in water regulation, osmoregulation, and photosynthesis. Integration of Weighted gene co-expression network analysis (WGCNA), Summary-data-based Mendelian Randomization (SMR) and GWAS, eQTLs identified 207 candidate causal genes as key regulators for WUE-related traits in wheat, such as TaMYB7-A1. Functional analyses found that TaMYB7-A1 enhances drought tolerance by promoting root growth, reducing oxidative stress, and improving osmotic regulation, enabling better water access and survival under stress. It also increases photosynthesis efficiency and WUE, boosting yield under drought without compromising performance in well-watered conditions, making it ideal target for breeding. Our findings provide a comprehensive omic framework for understanding the genetic architecture of WUE and drought resistance, offering valuable targets for breeding resilient wheat varieties.

plant biology↗

bioRxiv2024

Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult for the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA sequencing approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2 and NFKBIA that associated with mTOR pathway, inflammatory response and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, {gamma}-H2AX, {beta}-Gal and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of drug-resistant epilepsy patients with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent markers expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

neuroscience↗

bioRxiv2024

PlateletBase: A Comprehensive Knowledgebase for Platelet Research and Disease Insights

Platelets are vital in many pathophysiological processes, yet there is a lack of a comprehensive resource dedicated specifically to platelet research. To fill this gap, we have developed PlateletBase, a knowledge base aimed at enhancing the understanding and study of platelets and related diseases. Our team retrieved information from various public databases, specifically extracting and analyzing RNA-seq data from 3,711 samples across 41 different conditions available on NCBI. PlateletBase offers six analytical and visualization tools, enabling users to perform gene similarity analysis, pair correlation, multi-correlation, expression ranking, clinical information association, and gene annotation for platelets. The current version of PlateletBase includes 10,278 genomic entries, 31,758 transcriptomic entries, 4,869 proteomic entries, 2,614 omics knowledge entries, 1,833 drugs, 97 platelet resources, 438 diseases/traits, and six analysis modules. Each entry has been carefully curated and supported by experimental evidence. Additionally, PlateletBase features a user-friendly interface designed for efficient querying, manipulation, browsing, visualization, and analysis of detailed platelet protein and gene information. Case study results, such as those from gray platelet syndrome and angina pectoris, demonstrate that this tool can aid in identifying diagnostic biomarkers and exploring disease mechanisms, significantly advancing research in platelet functionality and its applications. PlateletBase is accessible at http://plateletbase.clinlabomics.org.cn/.

bioinformatics↗

bioRxiv2024

Bayesian Perspective for Orientation Estimation in Cryo-EM and Cryo-ET

Accurate orientation estimation is a crucial component of 3D molecular structure reconstruction, both in single-particle cryo-electron microscopy (cryo-EM) and in the increasingly popular field of cryo-electron tomography (cryo-ET). The dominant approach, which involves searching for the orientation that maximizes cross-correlation relative to given templates, is sub-optimal, particularly under low signal-to-noise conditions. In this work, we propose a Bayesian framework for more accurate and flexible orientation estimation, with the minimum mean square error (MMSE) estimator serving as a key example. Through simulations, we demonstrate that the MMSE estimator consistently outperforms the cross-correlation-based method, especially in challenging low signal-to-noise scenarios, and we provide a theoretical framework that supports these improvements. When incorporated into iterative refinement algorithms in the 3D reconstruction pipeline, the MMSE estimator markedly improves reconstruction accuracy, reduces model bias, and enhances robustness to the "Einstein from Noise" artifact. Crucially, we demonstrate that orientation estimation accuracy has a decisive effect on downstream structural heterogeneity analysis. In particular, integrating the MMSE-based pose estimator into frameworks for continuous heterogeneity recovery yields accuracy improvements approaching those obtained with ground-truth poses, establishing MMSE-based pose estimation as a key enabler of high-fidelity conformational landscape reconstruction. These findings indicate that the proposed Bayesian framework could substantially advance cryo-EM and cryo-ET by enhancing the accuracy, robustness, and reliability of 3D molecular structure reconstruction, thereby facilitating deeper insights into complex biological systems.

bioinformatics↗

bioRxiv2024

Multimodal, multifaceted Imaging-based Human Brain White Matter Atlas

Comparable to an atlas for navigating the Earth, a brain atlas outlines the brains neuroanatomical and functional landmarks. The tract-based brains white matter atlas (WMA) captures only tract boundaries, neglecting functionally relevant information, including emerging evidence on reliable neurodynamic detection in WM. Thus, a suitable WMA for functional investigations is needed. We delineated WM areas from coarse to fine-grained parcellations using local anatomical architecture and global functional dynamics using multimodal 7-Tesla magnetic resonance imaging in the Human Connectome Project. The multimodal WMA (MWMA) exhibited high between-subject consistency (69.1%) and test-retest reliability (93.1%), which aligned with the spatial pattern of chemoarchitectural homogeneity derived from open molecular imaging sources. Compared to a tract-based atlas, the MWMA better described the white matters cerebellum-association gradient axis, and precisely identified unique functional connectivity profiles of the corpus callosum. This improved MWMA will facilitate studies of WM functional organization, supporting cognition research and ultimately neuropathological vulnerability studies from a whole brain perspective.

neuroscience↗

bioRxiv2024

Neratinib, a clinical drug against breast cancer, protects against atherosclerosis via ASK1 inhibition

Atherosclerosis commences with endothelial dysfunction and the retention of cholesterol within the vessel wall, followed by a chronic inflammatory response. Cholesterol-lowering strategies (such as statins and PCSK9 inhibitors) are primarily used for treating patients with atherosclerotic cardiovascular diseases, but leaving the therapeutic dilemma of residual inflammatory risk. To address this challenge, we employed Connectivity Map (CMap) screening for inflammation mechanism-based anti-atherosclerotic compounds using perturbational datasets obtained from TNF and IL-1{beta}-stimulated human endothelial cells. This screening process allow us to identify Neratinib, a clinical drug against breast cancer, as the hit compound with potential anti-inflammatory actions in endothelial cells. Further studies reveal that Neratinib inhibited endothelial cell inflammation elicited by three different pro-inflammatory stimuli (TNF, IL-1{beta} and LPS). Intriguingly, the anti-inflammatory effect of Neratinib was independent of its classical target HER2/ERBB2 inhibition. Mechanistically, Neratinib directly binds ASK1 and suppresses ASK1 activation. In both male and female Ldlr-/- mice, treatment with Neratinib decreased the plaque area, reduced the necrotic core size and mitigated macrophage infiltration to stabilize plaques. Lastly, we observed that Neratinib, in conjunction with the use of Rosuvastatin (a standard lipid-lowering drug), led to a reduction in serum lipids, and produced synergistic anti-atherosclerotic effects. Olink proteomics study suggested that combination treatment alleviated inflammation-related cytokines/chemokines in the serum from Ldlr-/- mice. Taken together, these findings support the concept that Neratinib could be tested for its potential as a "repurposed" drug for vascular inflammation and atherosclerosis, thereby streamlining efforts to translate preclinical discoveries to clinical testing in humans. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/622073v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@78ef07org.highwire.dtl.DTLVardef@194f56forg.highwire.dtl.DTLVardef@7d65e4org.highwire.dtl.DTLVardef@ac7fe3_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryNeratinib protects against atherosclerosis by reducing endothelial inflammation via ASK1 inhibition

pharmacology and toxicology↗

bioRxiv2024

Brain functional connectivity as a mediator between hematological metrics and cognitive decline in children with beta-thalassemia major

Children with beta-thalassemia major ({beta} -TM) are at risk of cognitive impairment, particularly in learning and memory. While cognitive deficits in the general population have been extensively studied, brain-based predictors for {beta}-TM children remain unexplored. This study used connectome-based predictive modeling (CPM) to examine whole-brain functional connectivity in 60 participants to predict cognitive performance. {beta}-TM children showed impaired cognitive abilities, as evidenced by lower Wechsler Intelligence Scale scores compared to controls. The identified brain regions, though not typically linked to cognitive performances, exhibited functional connectivity patterns associated with {beta}-TM, as confirmed by network-based statistics. Correlations between task performance, functional connectivity identified by the CPM, and hematological metrics were also examined. Significant correlations were found between the strength of functional network identified by CPM and hematological metrics, particularly hemoglobin levels and red blood cell distribution width. The study demonstrates that hematological factors influence cognitive performance indirectly through specific functional connectivity, providing new insights into the neural underpinnings of cognitive deficits in children with beta-thalassemia major.

neuroscience↗

bioRxiv2024

Colchicine Inhibits Smooth Muscle Cell Phenotypic Switch and Aortic Dissection in Mice

Aortic dissection is a serious cardiovascular disease characterized by intimal tearing and vascular delamination. Smooth muscle cell phenotypic transformation, extracellular matrix degradation and vascular inflammation are the main pathogenic mechanisms of aortic dissection. Colchicine is an alkaloid derived from the plant Colchicum autumnale L. and was the first FDA-approved anti-inflammatory drug in the cardiovascular field. In this study, we investigated the protective effects of colchicine in aortic dissection in mice and found that colchicine resisted aortic dissection by inhibiting vascular inflammation and smooth muscle cell phenotypic transformation, and that colchicine reversed smooth muscle cell phenotypic transformation by targeting the transcriptional activator myocardin. This study provides new directions for the development of drug therapies for aortic dissection.

molecular biology↗

bioRxiv2024

In vivo genome editing of human hematopoietic stem cells for treatment of blood disorders by mRNA delivery

Ex vivo autologous hematopoietic stem cells (HSCs) gene therapy provides promising new treatments for hematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and significant side effects. Here, we developed an antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the HBG target in human HSCs to reactivate fetal hemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized structure LNPs achieves efficient in vivo base editing of HBG in transfusion-dependent {beta}-thalassemia (TDT) patients derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicated that utilizing LNPs for delivery of genome editor achieves efficient editing of endogenous genes of human HSCs. Notably, this non-viral delivery system eliminates the need for harvesting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders like sickle cell disease (SCD) and TDT. HighlightsO_LIAntibody-free targeted LNPs system achieves efficient mRNA delivery and base editing in human bone marrow cells including HSCs via one-time intravenous injection. C_LIO_LIDelivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG in TDT patients derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. C_LIO_LILNPs efficiently deliver gene editing system to the BM for in vivo editing of human HSCs, providing preclinical evidence for the next generation non-viral gene therapy for blood disorders. C_LI

bioengineering↗

bioRxiv2024

Clathrin-independent endocytosis and retrograde transport in cancer cells promote cytotoxic CD8 T cell activation

Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated CIE) contributes to the internalization of immunoglobulin-like proteins, including key immune synapse components. Here, we identify ICAM1 as a novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both proteins subsequently follow retromer-dependent retrograde transport to the trans-Golgi network (TGN) in cancer cells. From there, we propose that they undergo polarized redistribution to the plasma membrane, where they contribute to immune synapse formation between cancer cells and cytotoxic CD8 T cells. Disruption of EndoA3 or retromer components significantly affects the response of autologous cytotoxic CD8 T cells, as evidenced by reduced cytokine production and secretion, but increased lytic activity, while proliferation and later activation marker expression remain intact. This is accompanied by diminished ICAM1 density at the immune synapse, where we observe it arriving via polarized vesicular transport, indicating altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated CIE or retromer form enlarged immune synapses that fail to sustain full T cell cytokine secretion, suggesting a compensatory attempt by T cells to overcome the defective synapse, while likely promoting more transient contacts that potentially favor serial killing. Together, these findings reveal that EndoA3-mediated CIE and retrograde transport act in concert in cancer cells to relocate immune synapse components via the Golgi, thereby fine-tuning the balance between cytotoxic T cell cytokine secretion and lytic activity. These insights contribute to a better understanding of the mechanisms governing immune synapse formation and organization, providing a necessary foundation for the long-term identification of new strategies to enhance T cell-mediated anti-tumor immunity. Significance StatementThis study uncovers a novel mechanism by which clathrin-independent endocytosis (CIE) and retrograde transport collaborate to regulate immune synapse dynamics in cancer cells. We identify ICAM1 as a new cargo of Endophilin A3-mediated CIE, highlighting its role in the polarized redistribution of immune synapse components critical for cytotoxic CD8 T cell activation. By linking a specific CIE mechanism and retrograde transport to immune synapse function, our findings provide new insights into cancer-immunity interactions and suggest potential therapeutic strategies to enhance immune responses by targeting protein trafficking pathways.

cell biology↗

bioRxiv2024

An adaptive autoregressive diffusion approach to design active humanized antibody and nanobody

Humanization is a critical process for designing efficiently specific antibodies and nanobodies prior to clinical trials. Developing widely recognized deep learning techniques or frameworks for humanizing conventional antibodies and nanobodies presents a valuable yet challenging task. Inspired by the effectiveness of diffusion models across various applications, we introduce HuDiff, an adaptive diffusion approach for humanizing antibodies and nanobodies from scratch, referred to as HuDiff-Ab and HuDiff-Nb, respectively. This approach begins the humanization process exclusively with complementarity-determining region (CDR) sequences, eliminating the need for humanized templates. On public benchmark datasets, the results of HuDiff-Abs humanized antibodies are more similar to experimentally humanized antibodies than to those of the Sapiens humanization model. Besides, humanized nanobodies produced by HuDiff-Nb exhibit a higher humanness score and greater nativeness than those generated by the Lammanade pipeline for humanization nanobody. We apply HuDiff to humanize a mouse antibody and an alpaca nanobody, both targeting the SARS-CoV-2 RBD, and validate the binding affinity of humanized sequences through Bio-Layer Interferometry (BLI) experiments. The results show the binding affinity of the best humanized antibody is nearly equal to that of the parental mouse antibody (0.15 nM vs. 0.12 nM). Remarkably, the top-performing humanized nanobody exhibits a significantly enhanced binding affinity compared to the parental alpaca nanobody (2.52 nM vs. 5.47 nM), representing a 54% increase. These findings indicate that our approach HuDiff is highly effective in enhancing the humanness of antibodies and nanobodies while maintaining or potentially improving the binding affinity of the designed humanized sequences. The code and checkpoints of HuDiff are available at https://github.com/TencentAI4S/HuDiff.

bioinformatics↗

bioRxiv2024

Pan-Prediction of MHC-II Restricted Epitopes Across Species via an Alphafold-based Quantification Scheme

Predicting MHC-II restricted epitopes across species used to be challenging, but Alphafold (AF) may provide a structure-based pan-prediction solution. In this study, we established the new tool AF-pred with a clear standard for quantitative prediction results. Compared to the sequence-based tools heavily trained with human ligandome, AF-pred does not show advantage in predicting the binding patterns of human HLA-II but has far better performance in predicting binding patterns of other animals MHC-II. Using recently resolved bat MHC-II structures, we analyzed AF-preds prediction capability, logic and limitation. In addition, we also explored the impact of AF algorithm iterations on the prediction of MHC-II restricted epitopes. The results demonstrated that AF-pred is capable of cross-species prediction of MHC-II restricted epitopes and is conducive to the development of novel veterinary vaccines.

immunology↗

bioRxiv2024

Genomic and evolutionary evidence for drought adaptation of grass allopolyploid Brachypodium hybridum

Climate change increases the frequency and severity of drought worldwide, threatening the environmental resilience of cultivated grasses. However, the genetic diversity in many wild grasses could contribute to the development of climate-adapted varieties. Here, we elucidated the impact of polyploidy on drought response using allotetraploid Brachypodium hybridum (Bh) and its progenitor diploid species B. stacei (Bs). Our findings suggest that progenitor species genomic legacies resulting from hybridization and whole-genome duplications conferred greater ecological adaptive advantages to Bh over Bs. Genes related to stomatal regulation and immune response from S-subgenomes were under positive selection during speciation, underscoring their evolutionary importance in adapting to environmental stresses. Biased expression in polyploid subgenomes [B. stacei-type (Bhs) and B. distachyon-type (Bhd)] significantly influenced differential gene expression, with the dominant subgenome exhibiting more differential expression. B. hybridum adapted a drought escape strategy characterized by higher photosynthetic capacity and lower WUEi than Bs, driven by a highly correlated co-expression network involving genes in the circadian rhythm pathway. In summary, our study showed the influence of polyploidy on ecological and environmental adaptation and resilience in model Brachypodium grasses. These insights hold promise for informing the breeding of climate-resilient cereal crops and pasture grasses.

evolutionary biology↗

bioRxiv2024

Weakened airway epithelial junctions and enhanced neutrophil elastase release contribute to age-dependent bacteremia risk following pneumococcal pneumonia

Streptococcus pneumoniae (Sp; pneumococcus), the most common agent of community-acquired pneumonia, can spread systemically, particularly in the elderly, highlighting the need for adjunctive therapies. The airway epithelial barrier defends against bacteremia and is dependent upon apical junctional complex (AJC) proteins such as E-cadherin. After mouse lung challenge, pneumolysin (PLY), a key Sp virulence factor, stimulates epithelial secretion of an inflammatory eicosanoid, triggering the infiltration of polymorphonuclear leukocytes (PMNs) that secrete high levels of neutrophil elastase (NE), thus promoting epithelial damage and systemic infection. Here, pulmonary E-cadherin staining of intratracheally inoculated mice revealed PLY-mediated disruption of AJC independently of PMNs. Apical infection of air-liquid interface (ALI) respiratory epithelial monolayers similarly showed that PLY disrupts AJCs. This epithelial damage promoted PMN transmigration and bacterial apical-to-basolateral translocation, and pharmacologically fortifying epithelial barrier function diminished both barrier breach in vitro and bacteremia in vivo. E-cadherin staining after Sp intratracheal inoculation of >20-month-old mice, or apical infection of ALI monolayers derived from these mice, revealed an age-associated vulnerability to PLY-mediated AJC disruption, which in turn enhanced PMN migration and bacteremia. In addition, we found that PMNs from aged mice secrete increased levels of tissue-damaging NE. Simultaneous pharmacological inhibition of tissue-destructive NE and fortification of pulmonary epithelial barrier function was required to reduce the level of Sp bacteremia in aged mice to that of young mice. This work underscores the importance of fully characterizing the multifactorial sources of age-associated susceptibility in devising adjunctive therapies to mitigate invasive pneumococcal disease in the elderly.

microbiology↗