Biology subjects

Chen, P.

Publications and source records attributed to Chen, P..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

The mouse pangenome reveals the structural complexity of the murine protein coding landscape

We present the first mouse pangenome consisting of 17 high-quality inbred mouse strain genomes with complete annotation. This collection includes 12 widely used classical laboratory strains and 5 wild-derived strains. We have fully resolved previously incomplete genomic regions, including the major histocompatibility complex (MHC), the defensin cluster, T-cell receptor, and Ly49 complexes. Hundreds of non-reference genes identified in previous publications not found in GRCm39, like Defa1, Raet1a, and Klra20 (Ly49T), were localised in the new reference genomes. We conducted the first genome-wide scan of variable number tandem repeats (VNTRs) within the coding regions of mice, identifying over 400 genes with VNTR polymorphisms up to more than 600 repeat copies and repeat units reaching 990 nucleotides. Our strain-specific annotations enhance RNA-Seq analyses, as demonstrated in PWK/PhJ, where we observed a 5.1% improvement in read mapping and expression level differences in 2.1% of coding genes compared to using GRCm39.

genomics↗

bioRxiv2025

Virion stripping: A new role for bacterial proteases

We demonstrate that proteases produced by the oro-pharyngeal bacterial colonizer Porphyromonas gingivalis (Pg) reduce viral burden and modulate host interferon responses during respiratory syncytial virus (RSV) infection. Several oral bacteria, including Pg, have been shown to translocate to the upper airways through sub-clinical micro-aspiration. Our findings reveal that Pg, upon translocating to this new niche, significantly attenuated lung damage by reducing viral loads during respiratory viral infections in the lungs of wild-type mice. This protective effect was attributed to the activity of gingipains, cysteine endopeptidases produced by Pg, which cleaved envelope glycoproteins on RSV as well as on related murine-specific Sendai virus (SeV), thereby impairing their infectious capacity. Notably, the reduction in viral loads was independent of interferon lambda (IFN-{lambda}) signaling, which is actively suppressed by Pg in airway epithelial cells. However, the complete absence of IFN-{lambda} signaling resulted in a stronger inflammatory response despite a low viral load. Thus, we show a previously undescribed role for the oro-respiratory bacterial colonizer Pg in creating bottlenecks to viral infection by the activity of its proteases. SIGNIFICANCE STATEMENTReciprocal interactions between microbial colonizers and host epithelial cells are critical for providing initial defense against viral infections. However, our understanding of this phenomenon has been limited to microbiota-derived ligands that activate host pattern recognition receptors (PRRs), inducing basal interferon expression and downstream antiviral genes. Here, we present a novel mechanism that relies on microbial proteases to directly reduce viral load. Specifically, we discovered that the infectious capacity of the Respiratory Syncytial Virus (RSV) was significantly inhibited upon contact with the proteases (gingipains) produced by the oropharyngeal colonizer Porphyromonas gingivalis. Gingipains caused proteolytic degradation of the RSV envelope and attachment proteins, rendering them inactive. This preemptive reduction in viral infectious capacity consequently diminished the severity of respiratory viral infections in an IFN-independent manner.

microbiology↗

bioRxiv2025

N6-methyladenosine primes the malaria parasite for transmission

Sudden environmental changes are a recurring challenge for unicellular organisms, but a necessity for many to progress through their lifecycle. To transmit from its human host to mosquito vector, malaria parasites differentiate into male and female, semi-quiescent stages that can re-initiate development within seconds after transmission. Here, we identify the RNA modification N6-methyladenosine (m6A) as the mediator of a rapid, sex-specific, and temperature-sensitive mechanism to restructure protein synthesis during transmission. We find that male parasites maintain high levels of translation during their semi-quiescence that are rapidly repressed following mosquito uptake. This translational shutdown is essential for the continuation of male parasite development and depends on the m6A-binding protein YTH.2. We further show that m6A and YTH.2 are already present prior to transmission, but that their repressive interaction requires a temperature drop accompanying the exit from the human host. Hence, m6A appears to prime the parasite transcriptome and subsequently converts an environmental shift into a rapid translational response.

molecular biology↗

bioRxiv2025

Homoharringtonine Promotes FTO Degradation to Suppress LILRB4-Mediated Immune Evasion in Acute Monocytic Leukemia

Acute monocytic leukemia (AML-M5), a subtype of acute myeloid leukemia, is a highly aggressive malignancy characterized by a poor prognosis, primarily due to the ability of leukemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signaling pathway in monocytic AML. Utilizing RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8+ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8+ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/643466v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@e72e5dorg.highwire.dtl.DTLVardef@19519aeorg.highwire.dtl.DTLVardef@1c8f786org.highwire.dtl.DTLVardef@f2a963_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Gene expression plasticity in the antibiotic environment is predominantly adaptive in the budding yeast

Phenotypic plasticity plays a key role in adaptation to fluctuating environments. However, its evolutionary significance remains debated, with conflicting views on whether it is actively maintained by natural selection or a neutral consequence of molecular constraints. In this study, we investigate the evolutionary role of gene expression plasticity in yeast populations exposed to antibiotic and osmotic stress. Using mutation accumulation (MA) lines to separate the effects of natural selection from genetic drift, we compare gene expression responses (referred to as plastic change) between 22 natural strains, 21 MA lines, and their progenitor under non-stressed and stressed conditions. Our results show that, in the antibiotic environment, gene expression plasticity is selectively maintained, as indicated by its reduction in magnititude, reversal in directionality, and loss of stress-responsive pathways in MA lines. In contrast, plasticity in the osmotic stress condition appears neutral, with random variation across MA lines. This study provides direct evidence for the adaptive role of gene expression plasticity in the antibiotic environment and sheds light on its molecular mechanisms.

evolutionary biology↗

bioRxiv2025

Harnessing Neutrophils to Deliver Antibiotics Non-Invasively across the Tympanic Membrane for Otitis Media Treatment

Acute otitis media (AOM) is a leading cause of pediatric antibiotic prescriptions. Systemic antibiotics cause side effects and antibiotic resistance, whereas local delivery of antibiotics (directly to the middle ear) is hindered by an impermeable biological barrier, the tympanic membrane (TM). Here, we report on a liposome that hitchhikes on neutrophils to deliver antibiotics to the site of infection. Distinct from previous immune-cell-based therapies, we enable neutrophil hitchhiking via a topical application of hydroxylated liposomes, thus bypassing the invasive neutrophil harvesting procedures. The hydroxylated liposomes are opsonized by the complement protein fragments and subsequently internalized by native neutrophils. A simple topical application completely cures AOM in an established chinchilla model. It points to a low-cost and non-invasive treatment for this prevalent disease, poised to reduce pediatric antibiotic usage.

bioengineering↗

bioRxiv2025

Cellular Respiration and Amino Acid Metabolism Is Altered by Dietary Oligosaccharides in Salmonella During Epithelial Association

Dietary prebiotic oligosaccharides are common in peoples diets; however, little is known about how different prebiotics alter the enteric epithelium and microbiome. Here we show two structurally different prebiotic oligosaccharides, human milk oligosaccharides (HMO) and mannanoligosaccharides (MOS), alter the metabolism of colonic epithelial cells and Salmonella enterica sv. Typhimurium in ways specific to each prebiotic. Initially, HMO and MOS addition decreased S. Typhimurium association with epithelial cells. However, gene expression analysis revealed significantly induced expression of Specific Pathogenicity Island (SPI) 1 and 2 with HMO treatment opposed to increased fimbriae expression with MOS treatment. MOS treatment induced the expression of genes for amino acid metabolism in both the host cells and in S. Typhimurium, a metabolic shift that was not observed in the HMO treated cells. MOS treatment also altered respiration metabolism in S. Typhimurium to be more closely aligned to those observed in vivo during gut inflammation, which is opposed to colonization-type expression with HMO. Alteration of virulence observed was found to be prebiotic specific and dose dependent, indicating that some dietary substrates likely alter specific pathogens to change their virulence potential in unanticipated ways that lead to multiple outcomes to potentiate or attenuate enteric infections.

microbiology↗

bioRxiv2025

Hyperglycemia-Driven Hepatic Immune Dysfunction Facilitates Microbial Dissemination Post-Myocardial Infarction

BackgroundThe gut microbiome is intimately connected to cardiovascular health through the gut-heart axis and plays a pivotal role in maintaining homeostasis. Myocardial infarction (MI) disrupts this homeostatic balance, leading to widespread adverse effects. Hyperglycemia, a hallmark of metabolic dysfunction, further exacerbates these disruptions, emphasizing the need to understand the underlying mechanisms to develop effective therapeutic strategies for mitigating the cascading complications along the gut-heart axis. This study aims to elucidate the dynamics of gut barrier disruption during MI, and explore the livers function as an immune sentinel in this process, with a focus on the impact of hyperglycemia on microbial dissemination, systemic inflammation, and liver immune function. MethodsA murine MI model was used to evaluate gut permeability, bacterial translocation, and hepatic immune responses. MI was induced via permanent left anterior descending artery ligation. Hyperglycemia was established through streptozotocin injections and a high-fat, high-sugar diet. Gut barrier integrity was assessed using FITC-dextran assays, and microbial translocation was tracked through intravital imaging and anaerobic bacterial cultures from multiple organs. Hepatic immune function was analyzed via flow cytometry, cytokine profiling, and phagocytosis assays. 16S rRNA sequencing characterized the composition of translocated bacteria. ResultsMI significantly increased intestinal permeability, with hyperglycemia further exacerbating gut barrier dysfunction. Intravital imaging revealed bacterial translocation through the portal vein to the liver, highlighting the livers role in microbial interception. Hyperglycemia impaired hepatic macrophage function by activating NLRP3 inflammasome signaling, reducing bacterial clearance and promoting persistent liver colonization. Systemic inflammatory cytokines, particularly TNF-, were elevated, further facilitating microbial dissemination. 16S rRNA sequencing demonstrated host-dependent stochastic variability in translocated bacterial composition. ConclusionThe liver serves as a key immune regulator in the gut-liver-heart axis but is functionally compromised under hyperglycemia, exacerbating systemic inflammation and microbial dissemination post-MI. Targeting NLRP3 signaling and restoring gut barrier integrity may mitigate post-MI complications, particularly in hyperglycemic conditions. These findings underscore the need for integrated therapeutic strategies incorporating metabolic control and microbiome-targeted interventions to improve post-MI outcomes.

immunology↗

bioRxiv2025

Conformation-gated binding drives negative cooperativity in ATP:cob(I)alamin Adenosyltransferase for optimized cobalamin handling

Vitamin B12 (cobalamin) is a high-value yet scarce cofactor required for various metabolic processes, making its efficient handling important for maintaining metabolic homeostasis. While the involvement of ATP:cob(I)alamin adenosyltransferases (MMAB) in the synthesis, delivery, and repair of 5-deoxyadenosylcobalamin (AdoCbl) is well established, the kinetic mechanisms that regulate this process, particularly its negative cooperativity, remain poorly understood. Understanding these mechanisms is key to clarifying how MMAB efficiently uses AdoCbl, prevents resource wastage, and supports bacterial survival in nutrient-limited environments. Using single-molecule relative fluorescence (SRF) spectroscopy, we found that conformation-gated binding is the driving force behind MMABs preference for AdoCbl over hydroxocobalamin and is the underlying mechanism for negative cooperativity. This mechanism significantly slows down the binding of the second equivalent of AdoCbl, favoring the singly bound state. Our findings indicate that MMAB predominantly binds a single AdoCbl, optimizing the AdoCbl loading to methylmalonyl-CoA mutase. Additionally, our SRF approach also serves as a tool to explore other cofactor interactions, such as those between riboswitches and cobalamin derivatives, to provide insights into regulatory mechanisms of cobalamin sensing and gene regulation, which are crucial for bacterial adaptation to changing nutrient conditions. Significance StatementMMAB is important for B12-dependent propionate metabolism in bacteria. Our findings reveal that conformation-driven binding mechanism underlines the negative cooperativity of MMAB, as it favors the binding of the first AdoCbl while limiting further binding. The larger kon for the first site, combined with similar unbinding rates for both sites, could provide a solution for optimizing cobalamin handling and minimize unnecessary waste. Our single-molecule fluorescence approach offers a powerful tool for investigating other dynamic cofactor interactions, providing new insights into regulatory mechanisms in bacterial metabolism.

biophysics↗

bioRxiv2025

Spatiotemporal changes in soil properties predict plant health at continental scale

Abiotic and biotic soil properties are strong predictors of plant yield globally1-5, but they become unreliable over large areas when plant health is threatened by pathogen6-8. Here we present a novel approach to predict plant health based on spatiotemporal changes in soil chemical and biological properties. We first demonstrate that plant health and soil properties consistently respond to environmental change (organic fertilization) regardless of the soil type or geographical origin. Second, we experimentally show that trackable shifts in soil properties reliably explain soil suppressiveness to the Ralstonia solanacearum bacterial pathogen and that a scalable spatiotemporal model predicts plant health with 84% accuracy across multiple climatic zones and cropping systems. Our results suggest that this tight coupling between soil properties and plant health could facilitate the development of agricultural practices aimed at sustainably improving crop yields while safeguarding crop health.

ecology↗

bioRxiv2024

Inverted topologies in sequential fitness landscapes enable evolutionary control

Adaptive populations rarely evolve in a static environment. Therefore, understanding and ultimately controlling the evolution of a population requires consideration of fluctuating selective pressures. The fitness landscape metaphor has long been used as a tool for representing the selective pressures a given environment imposes on a population. Much work has already been done to understand the dynamics of evolution on a single fitness landscape. More recently, evolution on fluctuating or sequentially applied landscapes has come to the fore of evolutionary biology. As more empirical landscapes are described, metrics for describing salient features of paired landscapes will have uses for understanding likely evolutionary dynamics. Currently, Pearson correlation coefficient and collateral sensitivity likelihoods are used to quantify topographical relatedness or dissimilarity of a pair of landscapes. Here, we introduce the edge flip fraction, a new metric for comparing landscapes, which quantifies changes in the directionality of evolution between pairs of fitness landscapes. We demonstrate that the edge flip fraction captures topographical differences in landscapes that traditional metrics may overlook which have important consequences for the trajectories of populations evolving on them. By applying this metric to both empirical and synthetic fitness landscapes, we show that it partially predicts the collateral sensitivity likelihoods and can inform the optimality of drug sequences. We show that optimal drug sequences that keep populations within lower fitness regions require shifts in evolutionary directions, which are quantified by the edge flip fraction. Edge flip fraction complements existing measures and may help researchers understand how populations evolve under changing environmental conditions, and could yield clues in the pursuit of evolutionary control.

evolutionary biology↗

bioRxiv2024

Convergent representations and spatiotemporal dynamics of speech and language in brain and deep neural networks

Recent studies have explored the correspondence between single-modality DNN models (speech or text) and specific brain networks for speech and language. The key factors underlying these correlations and their spatiotemporal evolution within the brain language network remain unclear, particularly across different DNN modalities. To address these questions, we analyzed the representation similarity between self-supervised learning (SSL) models for speech (Wav2Vec2) and language (GPT-2), against neural responses to naturalistic speech captured via high-density electrocorticography. Our results indicated high prediction accuracy of both types of SSL models relative to neural activity before and after word onsets. It was the shared components between Wav2Vec2.0 and GPT-2 that explained the majority portion of the SSL-brain similarity. Furthermore, we observed distinct spatiotemporal dynamics: both models showed high encoding accuracy 40 milliseconds before word onset, especially in the mid-superior temporal gyrus (mid-STG), which can be explained by the shared contextual components in the SSL models; the Wav2Vec2.0 also peaked at 200 milliseconds after word onset around the posterior STG, which was mainly attributed to the acoustic-phonetic and static semantic information encoded in the SSL models. These results highlight how contextual and acoustic-phonetic cues encoded in DNNs align with spatiotemporal neural activity patterns, suggesting a significant overlap in how artificial and biological systems process linguistic information.

neuroscience↗

bioRxiv2024

Coevolution of Drosophila-type Timeless with Partner Clock Proteins

Drosophila-type timeless (dTIM) is established key clock protein in fruit flies, regulating the rhythmicity and light-mediated entrainment. However, as indicated by functional experiments, its contribution to the clock differs in various insects. Therefore, we conducted a comprehensive phylogenetic analysis of dTIM across animals, dated its origin, gene duplications, and losses. We identified variable and conserved protein domains, and pinpointed animal lineages that underwent the biggest changes in the dTIM sequence. While dTIM modifications are only mildly affected by changes in the PER protein, even the complete loss of PER in echinoderms had no impact on dTIM. However, changes in dTIM always co-occur with the loss of CRYPTOCHROMES or JETLAG. This is exemplified by the remarkably accelerated evolution of dTIM in phylloxera and aphids. Finally, alternative d-tim splicing, characteristic of D. melanogaster temperature-dependent function, is conserved at least to some extent in Diptera, albeit with unique alterations. Altogether, this study pinpoints major changes that shaped dTIM origin and evolution.

evolutionary biology↗

bioRxiv2024

A Palette of Bridged Bicycle-Strengthened Fluorophores

Organic fluorophores are the keystone of advanced biological imaging. The vast chemical space of fluorophores has been extensively explored in seek of molecules with ideal properties. However, within the current molecular constraints, there appears to be a trade-off between high brightness, robust photostability, and tunable biochemical properties. Herein we report a general strategy to systematically boost the performance of donor-acceptor-type fluorophores by leveraging SO2 and O-substituted azabicyclo[3.2.1] octane auxochromes. These bicyclic heterocycles give rise to a collection of Bridged dyes (BD) spanning the UV and visible range with top-notch quantum efficiencies, enhanced water solubility, and tunable cell-permeability. Notably, these azabicyclic fluorophores showed remarkable photostability than its tetramethyl or azatidine analogue, at the same time completely resistant to oxidative photobluing rendered by the Bredts rule. Functionalized BD dyes are tailored for applications in single-molecule imaging, super-resolution imaging (STED and SIM) in fixed or live mammalian cells and plant cells, and live zebrafish imaging or chemigenetic voltage imaging. Synergizing with advanced imaging methods, the bridge bicycle dyes represent a versatile palette for biological researches.

biophysics↗

bioRxiv2024

Temporal Configuration as a New Feature of Sound: Psychological and Neurophysiological Evidence, Cross-species Consistency and Underlying Neuronal Mechanisms

Natural sounds are defined not only by their spectral content but also by their fine temporal structure. Here we show that millisecond-scale temporal configuration--defined by the ordering of inter-click intervals (ICIs) within a click train--behaves as a distinct auditory feature, conserved across species and emerging hierarchically along the auditory pathway. Human listeners reliably discriminated click trains that shared the same average ICI but differed in temporal configuration, and these differences elicited robust mismatch negativity (MMN) responses in an oddball paradigm, indicating automatic cortical deviance detection. Awake rats showed analogous MMN-like ECoG responses to configuration changes, demonstrating cross-species generality. Neuropixels recordings along the inferior colliculus-medial geniculate body-primary auditory cortex (IC-MGB-A1) axis revealed minimal configuration sensitivity in IC, intermediate sensitivity in MGB, and strong stimulus-specific adaptation to temporal configuration in A1. Reversible cooling of auditory cortex reduced configuration sensitivity in MGB, implicating corticothalamic feedback in shaping thalamic representations. Layer-resolved analyses further showed that supragranular A1 neurons carry stronger configuration-specific adaptation than infragranular neurons. These findings identify temporal configuration as a feature-like dimension of sound and delineate a hierarchical, feedback-dependent IC-MGB-A1 circuit architecture for encoding fine temporal structure in the mammalian brain.

neuroscience↗

bioRxiv2024

A signal of temporal integration in the human auditory brain: psychological insights, EEG evidence, and clinical application

Temporal integration, the process by which the auditory system combines sound information over a curtain period to form a coherent auditory object, is essential for coherent auditory perception, yet its neural mechanisms remain underexplored. We use a "transitional click train" paradigm, which concatenates two click trains with slightly differing inter-click intervals (ICIs), to investigate temporal integration in the human cortex. Using a 64-channel electroencephalogram (EEG), we recorded responses from 42 healthy participants exposed to regular and irregular transitional click trains and conducted change detection tasks. Regular transitional click trains elicited significant change responses in the human cortex, indicative of temporal integration, whereas irregular trains did not. These neural responses were modulated by ICI length, ICI contrast, and regularity. Behavioral data mirrored EEG findings, showing enhanced detection for regular conditions compared to irregular conditions and pure tones. Furthermore, variations in change responses were associated with decision-making processes. Temporal continuity was critical, as introducing gaps between click trains diminished both behavioral and neural responses. In clinical assessments, 22 coma patients exhibited diminished or absent change responses, effectively distinguishing them from healthy individuals. Our findings identify distinct neural markers of temporal integration and highlight the potential of transitional click trains for clinical diagnostics.

neuroscience↗

bioRxiv2024

Structural analyses of apolipoprotein A-IV polymorphisms Q360H and T347S elucidate the inhibitory effect against thrombosis

Apolipoprotein A-IV (apoA-IV) is an abundant lipid-binding protein in blood plasma. We previously reported that apoA-IV, as an endogenous inhibitor, competitively binds platelet IIb{beta}3 integrin from its N-terminal residues, reducing the potential risk of thrombosis. This study aims to investigate how the apoA-IVQ360H and apoA-IVT347S mutations affect the structure and function of apoA-IV. These mutations are linked to increased risk of cardiovascular diseases due to multiple single-nucleotide polymorphisms in the C-terminal region of apoA-IV. We postulate the structural hindrance caused by the C-terminal motifs may impede the binding of apoA-IV to platelets at its N-terminal binding site. However, the mechanistic impact of Q360H and T347S polymorphisms on this intermolecular interaction and their potential contribution to the development of cardiovascular disease have not been adequately investigated. To address this, recombinant forms of human apoA-IVWT, apoA-IVQ360H, apoA-IVT347S variants were produced, and the structural stability, dimerization, and molecular dynamics of the C-terminus were examined utilizing biophysical techniques including fluorescence anisotropy, fluorescence spectrophotometry, circular dichroism, and biolayer interferometry methods. Our results showed a deceased fraction of -helix structure in apoA-IVQ360H and apoA-IVT347S compared to the wildtype, and the inhibitory effect of dimerized apoA-IV on platelet aggregation was reduced in apoA- IVQ360H and apoA-IVT347S variants. Binding kinetics of examined apoA-IV polymorphisms to platelet IIb{beta}3 suggest a potential mechanism for increased risk of cardiovascular diseases in individuals with apoA-IVQ360H and apoA-IVT347S polymorphisms.

biochemistry↗

bioRxiv2024

Bacterial sensing via Neuronal Receptor Initiates Gut Mitochondrial Surveillance for Host Adaptation

Animals exist within a microbial world and are constantly challenged by pathogen infections. Microbe-mediated protection for against infection is the survival strategy for host. However, elucidating specific microbial molecules and understanding how they interact with the hosts intracellular surveillance system for protection is difficult but highly desirable. Here, by establishing "pathogen-like-bacteria" screening system, we identified E. coli mutants, including {Delta}ymcB, that act as "pathogen-like-bacteria" to defend animals against Pseudomonas aeruginosa PA14 infection by activating UPRmt. Additionally, through genetic screening, we identified neuronal transmembrane protein, MDSS-1, that is crucial for sensing {Delta}ymcB and activating intestinal UPRmt. Moreover, we demonstrated that MDSS-1 functions as a receptor in ASE neurons, responsible for detecting {Delta}ymcB. It then communicates microbial signals through neuropeptides, GPCR, Wnt signaling and endopeptidase inhibitors to trigger intestinal UPRmt, that defends the host animals against infections. Furthermore, Constitutionally activation of MDSS-1 in ASE neurons is sufficient to trigger intestinal UPRmt in animals, resulting in protection against infection. Our study uncovers an intriguing mechanism involving intracellular mitochondrial surveillance, where neuron-intestine crosstalk originates from ASE neurons to detect bacteria and combat pathogens. This study identifies a bacteria-sensing mechanism in neurons that regulates intestinal mitochondrial surveillance pathway for host adaptation. HighlightsO_LIEstablishment of "pathogen-like-bacteria" screening system in C. elegans C_LIO_LI{Delta}ymcB promotes animal defend against infections via triggering UPRmt C_LIO_LINeuronal MDSS-1, a single transmembrane protein, detects "pathogen-like-bacteria" C_LIO_LIActivated-MDSS-1 induces distant UPRmt via inter-tissue communication factors C_LI

physiology↗