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Gao, N.

Publications and source records attributed to Gao, N..

At least 37 records · Page 2Linked to original sources
bioRxiv2024

Early-life Microbiome-Derived HCA Enhances Type 3 Immunity via FXR-dependent m6A RNA methylation

The gut microbiome plays a crucial role in the development of intestinal immunity during early life, but the underlying mechanisms remain largely unknown. Here, we found oxygen consumption in neonatal rats by S. boulardii accelerated the colonization of the microbiome and the development of type 3 immunity, which protected against S. typhimurium. Microbiome maturation increased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and elevated the levels of Hyocholic acid (HCA). HCA promotes the development of {gamma}{delta}T and type 3 innate lymphoid cell (ILC3) by sustaining the stability of Rorc mRNA via the FXR-WTAP- N6-methyl-adenosine (m6A) axis. L. reuteri, a bacterium encoding BSH, was enriched by oxygen consumption in the intestine and promoted intestinal type 3 immunity. However, inhibition of BSH blocks the L. reuteri-induced development of intestinal type 3 immunity. These results reveal the role of microbiome-derived HCA in the regulation of intestinal type 3 immunity during early life.

microbiology↗
bioRxiv2024

Molecular mechanism of the flotillin complex in membrane microdomain organization

Flotillin-1 and flotillin-2 form hetero-oligomers to create flotillin membrane microdomains essential for endocytosis and protein sorting. However, the mechanisms of flotillin oligomerization and microdomain organization remain incompletely understood. Here, we present the cryo-EM structure of human flotillin complex, showing that flotillin-1 and -2 form a 44-mer, membrane attached, and dome-shaped structure that defines a 30-nm circular membrane domain. The cryo-ET data demonstrates that while attached to the cytoplasmic leaflet in situ, flotillin complexes possess intrinsic structural plasticity on the native membrane. Each flotillin complex may represent a fundamental unit of membrane microdomains, with their clustering enabling the formation of larger and more elaborate domains. We further reveal that phosphorylation at residues Y160 (flotillin-1) and Y163 (flotillin-2) may act as a molecular switch to modulate complex assembly, potentially regulating its function in endocytosis. These findings demonstrate the molecular mechanism of flotillin-mediated membrane segregation and microdomain formation, and suggest a previously unrecognized role of flotillin in sequestrating membrane proteins.

biochemistry↗
bioRxiv2024

Bacterial ADP-heptose initiates a revival stem cell program in the intestinal epithelium

The intestinal epithelium has an exceptional capacity to repair following injury, and recent evidence has suggested that YAP-dependent signaling was crucial for the expansion of Clu+ revival stem cells (revSCs) with fetal-like characteristics, which are essential for epithelial regeneration. However, neither the mechanism underlying where these revSCs emerge from nor the nature of the physiological cues that induce this revSC program, are clearly identified. Here, we first demonstrate that Alpk1 and Tifa, which encode the proteins essential for the detection of the bacterial metabolite ADP-heptose (ADP-Hep), were expressed by the stem cell pool in the intestinal epithelium. Treatment of intestinal organoids with ADP-Hep not only induced acute NF-{kappa}B pro-inflammatory signaling but also TNF-dependent apoptosis within the crypt, causing blunted proliferation and acute disruption of the crypt architecture, while also triggering induction of a revSC program. To identify the molecular underpinnings of this process, we performed single-cell RNA-seq analysis of ADP-Hep-treated organoids as well as lineage-tracing experiments. Our data reveal that ADP-Hep induced the specific ablation of the homeostatic intestinal stem cell (ISC) pool. Removal of ADP-Hep resulted in the rapid recovery of ISCs through dedifferentiation of Paneth cells, which transiently acquired revSC features and expressed nuclear YAP. Moreover, lineage tracing from Lyz1+ Paneth cells showed that ADP-Hep triggered Paneth cell de-differentiation towards pluripotent and proliferative cells in organoids. In vivo, revSC emergence in response to irradiation-induced injury was severely blunted in Tifa-deficient mice, suggesting that efficient epithelial regeneration in this model required detection of microbiota-derived ADP-Hep by the ALPK1-TIFA pathway. Together, our work reveals that Paneth cells can serve as the cell of origin for revSC induction in the physiological context of microbial stimulation, and that the transient loss of Alpk1-expressing ISCs is the initiating event for this regenerative process.

cell biology↗
bioRxiv2023

Liver Protects Cytoarchitecture, Neuron Viability and Electrocortical Activity in Post-Cardiac Arrest Brain Injury

BACKGROUNDBrain injury is the major reason for patient deaths in victims who survive after cardiac arrest. Clinical studies have shown that the presence of hypoxic hepatitis and pre-cardiac arrest liver disease is associated with increased mortality and inferior neurological recovery. However, how the liver might impact the pathogenesis of post-cardiac arrest is still unknown. METHODSAn in vivo global cerebral ischemia model was established to assess how simultaneous liver ischemia affected the recovery of brain ischemic injury. In addition, an ex vivo brain normothermic machine perfusion (NMP) model was established to evaluate how addition of a functioning liver might impact the circulation, cytoarchitecture, neuron viability and electrocortical activity of the reperfused brain post-cardiac arrest. RESULTSIn the in vivo model, we observed a larger infarct area in the frontal lobe, elevated tissue injury scores in the CA1 region, as well as increased intravascular immune cell adhesion in the reperfused brains with hepatic ischemia, compared to those without simultaneous hepatic ischemia. The results of the ex vivo model demonstrated that the addition of a functioning liver to the brain NMP circuit significantly reduced post-cardiac arrest brain injury, increased neuronal viability and improved electrocortical activity. Furthermore, we observed significant alterations in gene expressions and metabolites in the presence or absence of hepatic ischemia. CONCLUSIONSOur research highlights the crucial role of the liver in the pathogenesis of post-cardiac arrest brain injury. These findings shed lights on a cardio-pulmonary-hepatic brain resuscitation strategy for patients with cardiac arrest.

neuroscience↗
bioRxiv2023

Interferon epsilon restricts Zika virus infection in the female reproductive tract

Interferon {varepsilon} (IFN{varepsilon}) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections (STIs). Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFN{varepsilon} contributes to protection against ZIKV infection in vivo is unknown. Here, we show that IFN{varepsilon} plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFN{varepsilon} was expressed not only by epithelial cells in the FRT, but also by certain immune and other cells at baseline or after exposure to viruses or specific TLR agonists. IFN{varepsilon}-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal, but not subcutaneous ZIKV infection. IFN{varepsilon}-deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFN{varepsilon} protected Ifn{varepsilon}-/- mice and highly susceptible Ifnar1-/-mice against vaginal ZIKV infection, indicating that IFN{varepsilon} was sufficient to provide protection even in the absence of signals from other type I IFNs and in an IFNAR1-independent manner. Our findings reveal a potentially critical role for IFN{varepsilon} in mediating protection against transmission of ZIKV in the context of sexual contact. SignificanceInterferon {varepsilon} (IFN{varepsilon}), a unique Type I IFN that is highly expressed in the epithelium of the female reproductive tract (FRT), is thought to protect the host against sexually transmitted infections (STIs) but the mechanism of action is not defined. Zika virus (ZIKV), a causative agent for preterm birth and other severe diseases in pregnant women, can be spread through vaginal transmission. Here, we show that mice lacking the Ifn{varepsilon} gene have abnormal epithelial development and tissue architecture in the cervicovaginal tract. The role of IFN{varepsilon} in protecting host against ZIKV is FRT-specific and is independent of IFNAR1 signaling. Our findings suggest potential preventive strategies based on harnessing mucosal immunity against STIs.

immunology↗
bioRxiv2022

Structural basis for BIRC6 to balance apoptosis and autophagy

Caspase-9 is the initiator caspase for the intrinsic apoptotic cell death pathway, and is critical to the activation of effector caspases during apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor of Apoptosis Protein (IAP) BIRC6/BRUCE/Apollon not only inhibits apoptosis, but also promotes ubiquitination of the key autophagic protein LC3 and inhibits autophagy. Here we show that BIRC6 forms an anti-parallel U-shaped dimer in a 3.6-[A] cryo-EM structure with multiple previously unannotated domains, including a ubiquitin-like domain, and discover that the mitochondria-derived pro-apoptotic factor Smac/DIABLO binds BIRC6 by interacting with one BIR domain, two carbohydrate-binding modules and two helices in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not caspase 9, for binding BIRC6. BIRC6 strongly inhibits cellular activity of caspase 9, but weakly suppresses that of caspase 3. Meanwhile, BIRC6 binds LC3 through an LC3-interacting region, probably following dimer disruption of this BIRC6 region. Deficiency in LC3 ubiquitination promotes autophagy and autophagic degradation of BIRC6, and inhibits apoptosis. Moreover, induction of autophagy promotes autophagic degradation of both procaspase-9 and active caspase-9, but not of effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.

cell biology↗
bioRxiv2022

ExposomeX: Integrative Exposomic Platform Expediates Discovery of "Exposure-Biology-Disease" Nexus

Exposome has become the hotspot of next-generation health studies. To date, there is no available effective platform to standardize the analysis of exposomic data. In this study, we aim to propose one new framework of exposomic analysis and build up one novel integrated platform "ExposomeX" to expediate the discovery of the "Exposure-Biology-Disease" nexus. We have developed 13 standardized modules to accomplish six major functions including statistical learning (E-STAT), exposome database search (E-DB), mass spectrometry data processing (E-MS), meta-analysis (E-META), biological link via pathway integration and protein-protein interaction (E-BIO) and data visualization (E-VIZ). Using ExposomeX, we can effectively analyze the multiple-dimensional exposomics data and investigate the "Exposure-Biology-Disease" nexus by exploring mediation and interaction effects, understanding statistical and biological mechanisms, strengthening prediction performance, and automatically conducting meta-analysis based on well-established literature databases. The performance of ExposomeX has been well validated by re-analyzing two previous multi-omics studies. Additionally, ExposomeX can efficiently help discover new associations, as well as relevant in-depth biological pathways via protein-protein interaction and gene ontology network analysis. In sum, we have proposed a novel framework for standardized exposomic analysis, which can be accessed using both R and online interactive platform (http://www.exposomex.cn/).

bioinformatics↗
bioRxiv2022

Cryo-EM Structure of the 50S-HflX Complex Reveals a Novel Mechanism of Antibiotic Resistance in E. coli

Bacterial HflX is a conserved ribosome-binding GTPase involved in splitting ribosomal complexes accumulated under stress condition. However, the atomic details of its ribosomal interaction remain to be elucidated. In this work, we present a high-resolution structure of the E. coli 50S subunit bound with HflX. The structure reveals highly specific contacts between HflX and the ribosomal RNA, and in particular, an insertion loop of the N-terminal domain of HflX is situated in the peptidyl transferase center (PTC) and makes direct interactions with PTC residues. Interestingly, this loop displays steric clash with a few PTC-targeting antibiotics on the 50S subunit, such as chloramphenicol. Deletion of hflX results in hypersensitivity to chloramphenicol treatment, and a loop residue G154 of HflX is important for the observed chloramphenicol resistance. Overall, our results suggest that HflX could be a general stress response factor that functions in both stalled ribosome splitting and PTC antibiotic displacing.

cell biology↗
bioRxiv2022

Rab11 is essential to pancreas morphogenesis, lumen formation and endocrine mass.

The molecular links between tissue-level morphogenesis and the differentiation of cell lineages in the pancreas remain elusive despite a decade of studies. We previously showed that in pancreas both these processes depend on proper lumenogenesis. The Rab GTPase Rab11 has been shown to be essential to epithelial lumen formation in vitro, however few studies have addressed its functions in vivo and none have tested its requirement in pancreas. Here, we show that Rab11 is critical to proper pancreas development. Co-deletion of the Rab11 isoforms Rab11A and Rab11B in the developing pancreatic epithelium (Rab11pancDKO) results in ~50% neonatal lethality, and surviving adult Rab11pancDKO mice exhibit defective endocrine function. Loss of Rab11 in the embryonic pancreas results in morphogenetic defects of the epithelium linked to defective lumen formation and interconnection. In contrast to wildtype cells, Rab11pancDKO cells attempt to form multiple lumens, resulting in a failure to coordinate a single apical membrane initiation site (AMIS) between groups of cells. We show that these defects are due to failures in vesicle trafficking, as apical components remain trapped within Rab11pancDKO cells. Together, these observations suggest Rab11 directly regulates epithelial lumen formation and morphogenesis. Our report links intracellular trafficking to organ morphogenesis in vivo, and presents a novel framework for decoding pancreatic development. HIGHLIGHTSO_LIRab11Af/f;Rab11B-/-;Pdx1-Cre pancreas displays disruption of epithelial organization and reduction of endocrine cell mass. C_LIO_LILoss of Rab11 results in disruption of pancreatic lumen continuity due to a failure of lumen formation. C_LIO_LIEpithelial cells lacking Rab11 display abnormal polarity. C_LI

developmental biology↗
bioRxiv2022

Structural and mechanistic insights into the DNA glycosylase AAG-mediated base excision in nucleosome

DNA glycosylase engaging with damaged base marks the initiation of base excision repair. Nucleosome-based packaging of eukaryotic genome obstructs DNA accessibility, and how DNA glycosylases locate the substrate site on nucleosomes is currently unclear. Here, we report cryo-electron microscopy structures of nucleosomes bearing a deoxyinosine (DI) in various geometric positions and structures of them in complex with DNA glycosylase AAG. The apo nucleosome structures show that the presence of a deoxyinosine alone perturbs nucleosomal DNA globally, leading to a general weakening of the interface between DNA and the histone core and a greater flexibility to the exit/entry of the nucleosomal DNA. AAG makes use of this nucleosomal plasticity and imposes further local deformation of the DNA through the formation of the stable enzyme-substrate complex. Mechanistically, local distortion augment, translation/rotational register shift and partial opening of the nucleosome are employed by AAG to cope with substrate sites in fully exposed, occluded and complete buried positions, respectively. Our findings reveal the molecular basis for the DI-induced modification on the structural dynamics of the nucleosome and elucidate how DNA glycosylase AAG accesses damaged sites on the nucleosome with different solution accessibility.

molecular biology↗
bioRxiv2022

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Insulin is the essential treatment of Type 1 (T1D) and is often used in Type 2 Diabetes. For nearly five decades, efforts have been focused on replenishing {beta}-cells in T1D patients as a more durable treatment. Gut endocrine cells can be converted into insulin-producing cells, but their numbers are limited. In this study we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine, in addition to enteroendocrine cells. Accordingly, lineage tracing experiments show that, besides enterochromaffin cells, the Paneth/goblet lineage can undergo conversion to the insulin lineage upon genetic or pharmacologic Foxo1 ablation in mice. We leveraged these data to design a screening platform in organoids to accurately quantitate {beta}-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process by expanding the intestinal secretory lineage. We identified a triple blockade of FoxO1, Notch, and Tgf{beta} that, when tested in insulin-deficient diabetic animals resulted in a near-normalization of glucose levels, associated with the appearance of gut insulin-producing cells. The findings illustrate a therapeutic approach to replace insulin treatment in diabetes.

cell biology↗
bioRxiv2022

Structure and mechanism of a mitochondrial AAA+ disaggregase CLBP

The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space and functions to promote the solubilization of various mitochondrial proteins. CLPB deficiency by mutations is associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. The mechanism of CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo- tetradecamers in apo-state and is remodeled into homo-dodecamers upon binding to substrates. Conserved pore- loops on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of two amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

molecular biology↗
bioRxiv2021

Atomic-Resolution Prediction of Degrader-mediated Ternary Complex Structures by Combining Molecular Simulations with Hydrogen Deuterium Exchange

Targeted protein degradation (TPD) has emerged as a powerful approach in drug discovery for removing (rather than inhibiting) proteins implicated in diseases. A key step in this approach is the formation of an induced proximity complex, where a degrader molecule recruits an E3 ligase to the protein of interest (POI), facilitating the transfer of ubiquitin to the POI and initiating the proteasomal degradation process. Here, we address three critical aspects of the TPD process: 1) formation of the ternary complex induced by a degrader molecule, 2) conformational heterogeneity of the ternary complex, and 3) assessment of ubiquitination propensity via the full Cullin Ring Ligase (CRL) macromolecular assembly. The novel approach presented here combines experimental biophysical data--in this case hydrogen-deuterium exchange mass spectrometry (HDX-MS, which measures the solvent exposure of protein residues)--with all-atom explicit solvent molecular dynamics (MD) simulations aided by enhanced sampling techniques to predict structural ensembles of ternary complexes at atomic resolution. We present results demonstrating the efficiency, accuracy, and reliability of our approach to predict ternary structure ensembles using the bromodomain of SMARCA2 (SMARCA2BD) with the E3 ligase VHL as the system of interest. The simulations reproduce X-ray crystal structures - including prospective simulations validated on a new structure that we determined in this work (PDB ID: 7S4E) - with root mean square deviations (RMSD) of 1.1 to 1.6 [A]. The simulations also reveal a structural ensemble of low-energy conformations of the ternary complex within a broad energy basin. To further characterize the structural ensemble, we used snapshots from the aforementioned simulations as seeds for Hamiltonian replica exchange molecular dynamics (HREMD) simulations, and then perform 7.1 milliseconds of aggregate simulation time using Folding@home. The resulting free energy surface identifies the crystal structure conformation within a broad low-energy basin and the dynamic ensemble is consistent with solution-phase biophysical experimental data (HDX-MS and small-angle x-ray scattering, SAXS). Finally, we graft structures from the ternary complexes onto the full CRL and perform enhanced sampling simulations, where we find that differences in degradation efficiency can be explained by the proximity distribution of lysine residues on the POI relative to the E2-loaded ubiquitin. Several of the top predicted ubiquitinated lysine residues are validated prospectively through a ubiquitin mapping proteomics experiment.

biophysics↗
bioRxiv2021

Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs. Highlights* Long-term infected NHPs develop antibodies neutralizing up to 54% of HIV-1 strains * Antibody J038 binds one V2 loop on HIV-1 Env trimer in a unique "up" position * UCA of the J038 lineage effectively neutralizes the autologous virus * J038 lineage antibodies mature through gradually increased contact to glycans

immunology↗
bioRxiv2021

Structural insights into GlcNAc-1-phosphotransferase that directs lysosomal protein transport

GlcNAc-1-phosphotransferase (GNPT) catalyzes the initial step in the formation of the mannose-6-phosphate tag that labels [~]60 lysosomal proteins for transport. Mutations in GNPT cause lysosomal storage disorders such as mucolipidoses. However, the molecular mechanism of GNPT remains unclear. Mammalian GNPTs are 2{beta}2{gamma}2 hexamers in which the core catalytic - and {beta}-subunits are derived from GNPTAB. Here, we present the cryo-electron microscopy structure of the Drosophila melanogaster GNPTAB homolog (DmGNPTAB). Four conserved regions located far apart in the sequence fold into the catalytic domain, which exhibits structural similarity to that of the UDP-glucose glycoprotein glucosyltransferase (UGGT). Comparison with UGGT revealed a putative donor substrate-binding site, and the functional requirements of critical residues in human GNPTAB were validated using GNPTAB-knockout cells. DmGNPTAB forms an evolutionarily conserved homodimer, and perturbing the dimer interface undermines the maturation and activity of human GNPTAB. These results provide important insights into GNPT function and related diseases.

biochemistry↗
bioRxiv2020

Phase separation of Mer2 organizes the meiotic loop-axis structure of chromatin during meiosis I

Sexually reproducing organisms acquire genetic diversity through meiotic recombination during meiosis I, which is initiated via programmed DNA double-strand breaks (DSBs) induced by Spo11-containing machinery in each meiotic cell. The combination of programmed DSB sites in each meiotic cell must be diverse, which requires a certain degree of randomness in the distribution of DSBs. The formation of programmed DSBs requires a preestablished loop-axis structure of chromatin. Here, we demonstrate that the axial element protein Mer2 undergoes liquid-liquid phase separation in vitro and in vivo through its intrinsically disordered C-terminal domain. A DNA binding motif within its central domain is responsible for bringing DNA into Mer2 liquid droplets and Mer2-DNA complex could assemble into filamentous structures extending from the droplets. These results suggest that phase separation of Mer2 drives the formation of a droplet-loop structure of meiotic chromatin to facilitate and to diversify programmed DSB formation.

biophysics↗
bioRxiv2020

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in the Chinese national Expanded Program on Immunization since 2007. The recent recognition of severe disease syndromes associated with ZIKV, and the identification of ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential interaction between the two. In this study, we showed that SA14-14-2 is protective against ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive immune responses to ZIKV; however, it was cellular immunity that predominantly mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not result in significant cross-protection, but did mediate antibody dependent enhancement in vitro, though this did not have an adverse impact on survival. This study suggests that SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising avenue into developing a novel bivalent vaccine against both ZIKV and JEV. ImportanceJapanese encephalitis is a controllable disease in many countries in Asia, especially in China, where many people have Japanese encephalitis virus (JEV) immunity due to extensive JEV vaccination campaigns or natural exposure. Live-attenuated SA14-14-2 strain is a safe and effective vaccine recommended by the World Health Organization and has been vaccinated more than 600 million doses since 1989. As the prevalence of Zika virus (ZIKV) and rising risk in above regions, the cross-reactive immune response between these two antigenically closely related flaviviruses, JEV and ZIKV, should also be fully recognized, which is presumed to be based on those ambiguous cross-reactive immunity between dengue virus and ZIKV. In this study, we found that JEV SA14-14-2 vaccine conferred cross-protection against ZIKV challenge in mice, which is mainly due to cellular immunity rather than neutralizing antibody response. However, specific protective components or cooperation between components warrant to be explored in subsequent experiments. In conclusion, this study can provide important evidence for those who live in JEV-endemic areas and are at risk for ZIKV infection.

microbiology↗