Biology subjects

Jiang, Q.

Publications and source records attributed to Jiang, Q..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Secretory carrier membrane proteins assist with aquaporin trafficking in Arabidopsis.

Aquaporins belonging to the plasma membrane intrinsic protein (PIP) subfamily are channel proteins that control water flow across cells, allowing plants to rapidly adjust hydraulic conductivity and thereby sustain growth, gas exchange, and recovery from drought. We show that secretory carrier membrane proteins (SCAMP) regulate the abundance of the aquaporins and thereby water transport in Arabidopsis root cells. SCAMPs are evolutionarily conserved multi-spanning transmembrane proteins. In animal cells, they function in secretion, endocytosis and autophagy. Knowledge on their role in plants is restricted to localization and trafficking experiments in heterologous systems and few genetic perturbation experiments. Here, we analysed all five members of the Arabidopsis SCAMP family. We identified conserved tyrosine motifs assisting in transport to the plasma membrane and N-terminally located NPF motifs that are required for internalization. SCAMPs dimerize both at the plasma membrane and endosomes, and dimerization is required for their internalization. Functionally, several PIPs were identified as common targets of multiple SCAMP isoforms. Triple and quintuple scamp mutants show mild developmental delay under standard growth conditions, but they are less sensitive to drought-induced leaf wilting. This observation cannot be explained by altered stomatal dynamics or densities, nor by differential soil water content. However, scamp mutant root protoplasts contain less PIPs and swell less under hypotonic conditions compared to wild type, indicating reduced PIP plasma membrane levels. In conclusion, our research identifies the SCAMP membrane trafficking proteins as regulators of PIP abundance at the plasma membrane in root cells. We propose that the reduced PIP levels in the scamp mutants act as a priming mechanism, allowing them to respond better to conditions of reduced water availability.

plant biology↗

bioRxiv2025

Mycobacterial Metallophosphatase MmpE Acts as a Nucleomodulin to Regulate Host Gene Expression and Promote Intracellular Survival

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a major global health challenge. Nucleomodulins, bacterial effectors that target the host cell nuclei, are increasingly recognized as key virulence factors, but their roles in mycobacterial pathogenesis remain incompletely elucidated. Here, we characterize a hypothetical protein Rv2577 (designated MmpE) not only as a Fe3+/Zn2+-dependent metallophosphatase but also as a critical nucleomodulin involved in immune evasion and intracellular persistence. MmpE utilizes two nuclear localization signals, RRR20-22 and RRK460-462, to enter the host cell nucleus, where it binds to the promoter region of the vitamin D receptor (VDR) gene, thereby inhibiting host inflammatory gene expression. Additionally, MmpE regulates the PI3K-Akt-mTOR signaling pathway, thereby arresting lysosome maturation. These actions collectively facilitate immune suppression and promote mycobacterial survival in macrophages and in mice. Our findings identify MmpE as a conserved nucleomodulin in mycobacteria and reveal a novel mechanism of MmpE-mediated intracellular survival.

microbiology↗

bioRxiv2025

MimicNeoAI: An integrated pipeline for identifying microbial mimicry antigens and tumor neoantigen partners

Tumor-associated microbial antigens represent promising immunotherapy targets, yet systematic identification methods remain underdeveloped. We developed MimicNeoAI, a computational pipeline integrating BiLSTM networks to identify microbial epitopes, mutation-derived neoepitopes, and their microbial mimics from sequencing data. Training on validated epitope datasets yielded 0.90 AUC with 91% accuracy on experimental validation sets. Application to colorectal cancer revealed that microbial epitopes, despite originating from a nine-fold smaller peptide pool, generated twice the immunogenic candidates (153 vs 75) compared to mutation-derived neoepitopes. These microbial epitopes exhibited exclusive tumor-specificity with no overlap in normal tissues. Single-cell TCR sequencing confirmed clonal expansion against 75% of predicted highly immunogenic epitopes, with molecular dynamics simulations demonstrating positive correlation between predicted immunogenicity and HLA-epitope-TCR binding stability. Collectively, our pipeline systematically unveils abundant, tumor-specific, and highly immunogenic microbial epitopes, providing a computational framework for developing broadly applicable cancer immunotherapies that leverage the tumor microbiome as an untapped source of therapeutic targets.

bioinformatics↗

bioRxiv2025

A Conserved Mycobacterial Nucleomodulin Hijacks the Host COMPASS Complex to Reprogram Pro-Inflammatory Transcription and Promote Intracellular Survival

Nucleomodulins are a class of effector proteins secreted by bacterial pathogens that translocate into the host cell nucleus to modulate nuclear processes. However, their target proteins and underlying molecular mechanisms remain poorly understood in mycobacteria. Herein, we identified a conserved hypothetical protein Rv1075c, designated MgdE, as a nucleomodulin that enhances mycobacterial intracellular survival. MgdE undergoes nuclear translocation via two nuclear localization signals, KRIR108-111 and RLRRPR300-305, and interacts with ASH2L and WDR5, two subunits of the host histone methyltransferase COMPASS complex. This interaction suppresses histone H3 lysine 4 (H3K4) methylation-mediated transcription of pro-inflammatory genes, including IL6 and IL1B, thereby promoting mycobacterial survival in both macrophages and mice. Our study provides the first experimental evidence that a bacterial nucleomodulin facilitates intracellular survival by directly targeting the host COMPASS complex. These findings advance our understanding of mycobacterial pathogenesis by revealing a novel mechanism that contributes to its intracellular survival strategy.

microbiology↗

bioRxiv2025

PhysDock: A Physics-Guided All-Atom Diffusion Model for Protein-Ligand Complex Prediction

Accurate prediction of protein-ligand complexes remains a central challenge in structural biology. Traditional methods are computationally inefficient and prone to local minima, whereas deep learning approaches struggle to capture structural flexibility and physical plausibility. We introduce PhysDock, a physics-guided diffusion model that uniquely integrates (i) all-atom diffusion to model ligand flexibility and protein precision-flexibility (i.e., subtle conformational adjustments); (ii) physical priors as diffusion conditioning, alongside two-phase physics guidance during the denoising diffusion to ensure physical plausibility. PhysDock demonstrates state-of-the-art performance in redocking benchmarks and excels in the more challenging cross-docking assessments. For practical utility, PhysDock (i) resolves cannabinoid receptor selectivity across diverse molecules, achieving accuracy comparable to experiments; (ii) distinguishes most drug candidates from weak binders in virtual screening of NTRK3 kinase, while uncovering novel candidates with structural insights. PhysDock serves as a versatile tool for protein-ligand complex prediction, with substantial potential to accelerate structure-based drug discovery.

bioinformatics↗

bioRxiv2025

Temporal mapping of the anti-tumor effects of nanobody-based MSLN.CAR-T cell therapy in metastatic solid tumors

Studies on the dynamic changes occurring in the tumor microenvironment (TME) following CAR-T cell therapy have been confounded by host lymphodepletion, multiple dosing and immunodeficient models. Here, a nanobody-based, mouse mesothelin-targeting CAR-T cell (A101) was developed, achieving effective primary tumor suppression, metastasis reduction, and improved survival after a single dose in immunocompetent, syngeneic mouse models without lymphodepletion. Temporal tumor profiling using RNA sequencing revealed initial downregulation of cell proliferation genes followed by upregulation of inflammation, epithelial-to-mesenchymal-transition (EMT) and extracellular matrix (ECM) modification genes in the CAR-T-treated tumors relative to mock-T-treated controls. This phenotype was reversed at a later timepoint which coincided with downregulation of immunosuppressive Cd274+ Lcn2+ neutrophils and upregulation of anti-tumor P2rx1+ Nrf2- neutrophils. At the same time, upregulation of Ccl2+ in fibroblasts and a more immunomodulatory macrophage phenotype was observed in CAR-T-treated tumors, indicating a tumor adaptation mechanism. This study demonstrates complex dynamic changes in the TME, and highlights time-dependent responses of solid tumors to CAR-T cell therapy. It further highlights Lcn2+ neutrophils and Ccl2+ fibroblasts as potential therapeutic targets for improving CAR-T cell anti-tumor efficacy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/640438v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@88ec4org.highwire.dtl.DTLVardef@1d4fa64org.highwire.dtl.DTLVardef@182e11aorg.highwire.dtl.DTLVardef@1889182_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Tumor responses to A101 CAR-T cell treatment. C_FIG

immunology↗

bioRxiv2025

Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRASMULTI-ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.

cancer biology↗

bioRxiv2025

Anti- and Pro-tumor Functions of Distinct Regulatory T Cell Subsets in Colorectal Cancer

Regulatory T (Treg) cells contribute to solid organ cancer progression, except in colorectal cancer (CRC) despite being abundantly present. Here, we demonstrate that two distinct tumoral IL-10 and IL-10- Treg cell subsets exert opposing functions by counteracting and promoting CRC tumor growth, respectively. The tumor restraining activity of IL-10 Treg cells was mediated by their suppression of effector CD4 T cell production of IL-17, which directly stimulates CRC tumor cell proliferation. Consistently, IL-10- Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal tissues, whereas IL-10+ Treg cells exhibited the opposite distribution. Furthermore, relative abundance of IL-10 and IL-10- Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg cell subsets provides a rationale for therapeutic strategies to selectively target pro-tumoral Treg cells while preserving their anti-tumoral counterparts across barrier tissue cancers that harbor both subsets.

immunology↗

bioRxiv2025

Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8+ T cells in triple-negative breast cancer

Neoadjuvant immunotherapy seeks to harness the primary tumor as a source of relevant tumor antigens to enhance systemic anti-tumor immunity through improved immunological surveillance. Despite having revolutionized the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC), a significant portion of patients remain unresponsive and succumb to metastatic recurrence post-treatment. Here, we found that optimally scheduled neoadjuvant administration of anti-4-1BB monotherapy was able to counteract metastases and prolong survival following surgical resection. Phenotypic and transcriptional profiling revealed enhanced 4-1BB expression on tumor-infiltrating intermediate (Tint), relative to progenitor (Tprog) and terminally exhausted (Tterm) T cells. Furthermore, Tint was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of Tint, with reduced expression of tissue-retention marker CD103 in Tprog. This was accompanied by increased TCR clonotype sharing between paired tumors and pre-metastatic lungs. Further interrogation of sorted intratumor T cells confirmed enhanced T cell egress into circulation following anti-4-1BB treatment. In addition, gene signature extracted from anti-4-1BB treated Tint was consistently associated with improved clinical outcomes in BRCA patients. Combinatorial neoadjuvant anti-4-1BB and ablation of tumor-derived CXCL16 resulted in enhanced therapeutic effect. These findings illustrate the intratumor changes underpinning the efficacy of neoadjuvant anti-4-1BB, highlighting the reciprocity between local tissue-retention and distant immunologic fortification, suggesting treatment can reverse the siphoning of intratumor T cells to primary tumor, enabling redistribution to distant tissues and subsequent protection against metastases.

immunology↗

bioRxiv2025

Reusing wasted bioresources for crop protection: Calcinated oyster shell powder enhances rhizospheric microbial-mediated suppression of root-knot nematodes

The root-knot nematode (RKN) Meloidogyne incognita is one of the most destructive plant-parasitic nematodes (PPNs) affecting crop production worldwide. Our earlier study revealed that calcinated oyster shell powder (OSP) effectively suppressed tobacco RKN disease. However, the suppression mechanism of OSP against RKNs remain unknown. Our study revealed that calcinated OSP reduced the tobacco root-knot index by more than 38% by inhibiting the migration of second-stage juveniles of Meloidogyne incognita (J2) in the soil. Furthermore, OSP reduced the J2 density in the tobacco rhizosphere by 43.69% and significantly increased the soil pH by 0.68; moreover, OSP increased the contents of soil exchangeable calcium (ExchCa) and exchangeable magnesium (ExchMg) by more than 50%. Moreover, soil properties, including ExchMg, ExchCa and pH, enhanced the microbial-mediated suppression of J2. Specifically, Proteobacteria and Gemmatimonadota dominated the microbial community suppressing RKN, and fungal richness contributed to the suppression of RKNs; in addition, Chloroflexi and Acidobacteria dominated the microbial community promoting RKN prosperity. Our study revealed that the reuse of wasted oyster shell powder as an innovative antagonist is a promising avenue for ecofriendly RKN management strategies. IMPORTANCEThere is increased demand for ecofriendly RKN management strategies, and this study is the first to propose that the reuse of wasted oyster shell powder as an innovative antagonist against RKNs is effective, and calcinated oyster shell powder can reduce tobacco root-knot index and Meloidogyne incognita (J2) density by inhibiting the migration of J2s and enhancing the microbially mediated suppression of J2s in the tobacco rhizosphere. Moreover, several soil microbial and physicochemical indicators, including the contents of soil exchangeable calcium, exchangeable magnesium, pH and the relative abundance of Proteobacteria, Gemmatimonadota, Chloroflexi and Acidobacteria in plant rhizosphere were suggested to guide the development of ecofriendly PPN management strategies.

microbiology↗

bioRxiv2024

EpiAgent: Foundation model for single-cell epigenomic data

Large-scale foundation models have recently opened new avenues for artificial general intelligence. Such a research paradigm has recently shown considerable promise in the analysis of single-cell sequencing data, while to date, efforts have centered on transcriptome. In contrast to gene expression, chromatin accessibility provides more decisive insights into cell states, shaping the chromatin regulatory landscapes that control transcription in distinct cell types. Yet, challenges also persist due to the abundance of features, high data sparsity, and the quasi-binary nature of these data. Here, we introduce EpiAgent, the first foundation model for single-cell epigenomic data, pretrained on a large-scale Human-scATAC-Corpus comprising approximately 5 million cells and 35 billion tokens. EpiAgent encodes chromatin accessibility patterns of cells as concise "cell sentences," and employs bidirectional attention to capture cellular heterogeneity behind regulatory networks. With comprehensive benchmarks, we demonstrate that EpiAgent excels in typical downstream tasks, including unsupervised feature extraction, supervised cell annotation, and data imputation. By incorporating external embeddings, EpiAgent facilitates the prediction of cellular responses to both out-of-sample stimulated and unseen genetic perturbations, as well as reference data integration and query data mapping. By simulating the knockout of key cis-regulatory elements, EpiAgent enables in-silico treatment for cancer analysis. We further extended zero-shot capabilities of EpiAgent, allowing direct cell type annotation on newly sequenced datasets without additional training.

bioinformatics↗

bioRxiv2024

GABAergic neurons from the ventral tegmental area represent and regulate force vectors

The ventral tegmental area (VTA), a midbrain region associated with motivated behaviors, consists predominantly of dopaminergic (DA) neurons and GABAergic (GABA) neurons. Previous work has suggested that VTA GABA neurons provide a reward prediction, which is used in computing a reward prediction error. In this study, using in vivo electrophysiology and continuous quantification of force exertion in head-fixed mice, we discovered distinct populations of VTA GABA neurons that exhibited precise force tuning independently of learning, reward prediction, and outcome valence. Their activity usually preceded force exertion, and selective optogenetic manipulations of these neurons systematically modulated force exertion without influencing reward prediction. Together, these findings show that VTA GABA neurons continuously regulate force vectors during motivated behavior.

neuroscience↗

bioRxiv2024

Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

Chemoresistance is a major driver of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single cell culture to identify, retrieve, and RNA-Seq profile primary quiescent ovarian cancer cells (qOvCa). We found that many qOvCa differentially expressed genes are transcriptional targets of the Myocardin Related Transcription Factor/Serum Response Factor (MRTF/SRF) pathway. We also found that genetic disruption of MRTF-SRF interaction, or an MRTF/SRF inhibitor (CCG257081) impact qOvCa gene expression and induce a quiescent state in cancer cells. Suggesting a broad role for this pathway in quiescence, CCG257081 treatment induced quiescence in breast, lung, colon, pancreatic and ovarian cancer cells. Furthermore, CCG081 (i) maintained a quiescent state in patient derived breast cancer organoids and, (ii) induced tumor growth arrest in ovarian cancer xenografts. Together, these data suggest that MRTF/SRF pathway is a critical regulator of quiescence in cancer and a possible therapeutic target. SignificanceQuiescence is a critical driver of chemoresistance. The MRFT-SRF pathway regulates cancer cell quiescence and inhibiting the MRTF-SRF pathway can prevent the outgrowth of quiescent cancer cells and improve cancer outcomes.

cancer biology↗

bioRxiv2024

Pyramidal cell types and 5-HT2A receptors are essential for psilocybin's lasting drug action

Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1-4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells7-9. A key question is how these cellular modifications map onto cell type-specific circuits to produce psychedelics behavioral actions10. Here, we use in vivo optical imaging, chemogenetic perturbation, and cell type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex. We find that a single dose of psilocybin increased the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types. Behaviorally, silencing the PT neurons eliminates psilocybins ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolishes psilocybins effects on stress-related behavior and structural plasticity. Collectively these results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as playing essential roles for psilocybins long-term drug action.

neuroscience↗

bioRxiv2024

Precise amplification-free detection of highly structured RNA with an enhanced SCas12a assay

The CRISPR/Cas12a system has revolutionized molecular diagnostics; however, its application in directly detecting complex structured RNA remains challenging. Recently, we have developed a RNA detection method called SCas12a, which exhibits high sensitivity and efficiency in detecting RNA molecules devoid of intricate secondary structures. Here, we present an enhanced SCas12a assay (SCas12aV2) that facilitates precise amplification-free detection of highly structured RNA molecules. Our approach reengineers the split Cas12a system by optimizing the scaffold RNA length and targeting asymmetric RNA structures, thereby minimizing steric hindrance. We observe that utilization of a dsDNA-ssDNA hybrid DNA activator significantly enhances both the sensitivity and kinetics compared to those achieved using traditional ssDNA or dsDNA activators. The SCas12aV2 assay demonstrates exceptional sensitivity, with a limit of detection reaching 246 aM for pooled activators and 10 pM for single-site targeting. It also exhibits high specificity for single nucleotide polymorphisms (SNPs) and successfully identifies viable bacterial populations and SARS-CoV-2 infections from clinical samples. The assays versatility is further highlighted by its applicability to various Cas12a orthologs, including the thermostable CtCas12a. This work offers a significant advance in molecular diagnostics, enhancing the potential for accurate and efficient RNA detection.

molecular biology↗

bioRxiv2024

A Distinct Alternative mRNA Splicing Profile Identifies the Oncogenic CD44 Transcript Variant 3 in KMT2A-Rearranged Pediatric T-cell Acute Lymphoblastic Leukemia Cells

T-cell acute lymphoblastic leukemia (T-ALL), which constitutes of 10-15% of all pediatric ALL cases, is known for its complex pathology due to pervasive genetic and chromosomal abnormalities. Although most children are successfully cured, chromosomal rearrangements involving the KMT2A (KMT2A) gene is considered a poor prognostic factor. In a cohort of 171 pediatric T-ALL samples we have studied differences in gene and splice variant patterns in KMT2A rearranged (KMT2A-r) T-ALL compared to KMT2A negative (KMT2A-wt) T-ALL samples. Our results have identified a distinct gene expression and splice variant expression pattern in pediatric KMT2A-r patient samples including significant expression of splicing regulatory markers ESRP1 and MBNL3. Additionally, the pro-survival long transcript variant of BCL2 were upregulated in KMT2A-r compared to KMT2A-wt T-ALL samples. Lastly, increased levels of activating methylation in the promoter region of CD44 were identified followed by an upregulation of the oncogenic transcript variant CD44v3 in KMT2A-r T-ALL. Together this suggests that CD44v3 could play a potential role as gene expression-based risk stratification of KMT2A-r rearranged T-ALL and could possibly serve as a therapeutic target using splicing modulators.

cancer biology↗

bioRxiv2024

Transmission of Mixed Convergent Signals at the Mouse Retinogeniculate Synapse

There are two broad modes of information transfer in the brain: the labeled line model, where neurons relay inputs they receive, and the mixed tuning model, where neurons transform and integrate different inputs. In the visual pathway, information transfer between retinal ganglion cells (RGCs) and the dorsal lateral geniculate nucleus (dLGN) neurons is primarily viewed as a labeled line. However, recent work in mice has demonstrated that different RGC types, encoding distinct visual features, can converge onto a dLGN neuron, raising the fundamental question of whether the dLGN transforms visual information. Using optogenetics we activated distinct RGC populations and assessed spiking output of dLGN neurons by in vivo recordings. We found that visual response properties of dLGN neurons driven by a specific RGC population largely matched properties of the activated RGCs. Furthermore, in vitro dual-opsin experiments demonstrate that strong functional convergence from distinct RGC types rarely occurs. Thus, retinogeniculate information transfer in mice largely adheres to a labeled line model.

neuroscience↗

bioRxiv2024

Human microbiome-derived peptide affects the development of experimental autoimmune encephalomyelitis via molecular mimicry

BackgroundGut commensal microbiota has been identified as a potential environmental risk factor for multiple sclerosis (MS), and numerous studies have linked the commensal microorganism with the onset of MS. However, little is known about the mechanisms underlying the gut microbiome and host-immune system interaction. MethodsWe employed bioinformatics methodologies to identify human microbial-derived peptides by analyzing their similarity to the MHC II-TCR binding patterns of self-antigens. Subsequently, we conducted a range of in vitro and in vivo assays to assess the encephalitogenic potential of these microbial-derived peptides. FindingsWe analyzed 304,246 human microbiome genomes and 103 metagenomes collected from the MS cohort and identified 731 nonredundant analogs of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Of note, half of these analogs could bind to MHC II and interact with TCR through structural modeling of the interaction using fine-tuned AlphaFold. Among the 8 selected peptides, the peptide (P3) shows the ability to activate MOG35-55-specific CD4+ T cells in vitro. Furthermore, P3 shows encephalitogenic capacity and has the potential to induce EAE in some animals. Notably, mice immunized with a combination of P3 and MOG35-55 develop severe EAE. Additionally, dendritic cells could process and present P3 to MOG-specific CD4+ T cells and activate these cells. InterpretationOur data suggests the potential involvement of a MOG35-55-mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis. Our findings offer direct evidence of how microbes can initiate the development of EAE, suggesting a potential microbiome-based therapeutic target for inhibiting the progression of MS. FundingNational Natural Science Foundation of China (82371350 to GY) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSOn July 31, 2024, we conducted a search on PubMed for articles containing the phrases "gut microbiome and multiple sclerosis" and "gut microbiome and experimental autoimmune encephalomyelitis." This search yielded a total of 630 and 151 articles, respectively, indicating that the relationship between gut microbiota and the development of MS and EAE is well established. In contrast, our search for "gut microbiome and molecular mimicry and experimental autoimmune encephalomyelitis" revealed only two review papers, highlighting a significant gap in the literature regarding the role of molecular mimicry in connecting gut microbiome dynamics to the development of EAE. Added value of this studyIn this study, we employed bioinformatics tools to screen for microbial-derived peptides in the gut that potentially cross-react with autoantigen-specific TCR. Our key findings include: 1) Identification of MOG35-55 mimics within the human gut microbiome by employing a combination of TCR-binding footprint screening and prediction model of peptide-MHC II-TCR complexes; 2) Microbial-derived MOG35-55 mimics can cross-react with MOG35-55-specific CD4+ T cells; 3) Among them, peptide 3 predicted from Akkermansia muciniphila can induce moderate EAE in mice; 4) Dendritic cells could process and present peptide 3 to MOG-specific CD4+ T cells and activate these cells. Implications of all the available evidenceThis study suggests the potential involvement of a MOG35-55-mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis. These data may provide a potential microbiome-based therapeutic target for inhibiting the progression of MS.

immunology↗