Biology subjects

Zhao, Z.

Publications and source records attributed to Zhao, Z..

At least 379 records · Page 21Linked to original sources

bioRxiv2022

SRSF10 is essential for progenitor spermatogonia expansion by regulating alternative splicing

Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using germ cell-specific knockout mouse model, we demonstrated that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. Depletion of Srsf10 in germ cells had little effect on the formation of SSCs but impeded the expansion of progenitor spermatogonia, leading to the failure of spermatogonia differentiation and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Furthermore, the expression of genes involved in cell cycle was abnormal in all subtypes of spermatogonia identified in single-cell RNA-seq data. Notably, using isolated spermatogonia, we found that Srsf10 depletion disturbed the alternative splicing of hundreds of genes, which were preferentially associated with cell cycle, mitotic cell cycle checkpoint and germ cell development, including Dazl, Kit, Ret, Sycp1, Nasp and Bora. These data suggest that SRSF10 is critical for the expansion of progenitor spermatogonia by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.

developmental biology↗

bioRxiv2022

De-heterogeneity of the eukaryotic viral reference database (EVRD) improves the accuracy and efficiency of viromic analysis

Widespread in public databases, the notorious contamination in virus reference databases often leads to confusing even wrong conclusions in applications like viral disease diagnosis and viromic analysis, highlighting the need of a high-quality database. Here, we report the comprehensive scrutiny and the purification of the largest viral sequence collections of GenBank and UniProt by detection and characterization of heterogeneous sequences (HGSs). A total of 766 nucleotide- and 276 amino acid-HGSs were determined with length up to 6,605 bp, which were widely distributed in 39 families, with many involving highly public health-related viruses, such as hepatitis C virus, Crimea-Congo hemorrhagic fever virus and filovirus. Majority of these HGSs are sequences of a wide range of hosts including humans, with the rest resulting from vectors, misclassification and laboratory components. However, these HGSs cannot be simply considered as exotic contaminants, since part of which are resultants of natural occurrence or artificial engineering of the viruses. Nevertheless, they significantly disturb the genomic analysis, and hence were deleted from the database. A further augmentation was implemented with addition of the risk and vaccine sequences, which finally results in a high-quality eukaryotic virus reference database (EVRD). EVRD showed higher accuracy and less time-consuming without coverage compromise by reducing false positives than other integrated databases in viromic analysis. EVRD is freely accessible with favorable application in viral disease diagnosis, taxonomic clustering, viromic analysis and novel virus detection.

microbiology↗

bioRxiv2022

Development of a Method Combining Peptidiscs and Proteomics to Identify, Stabilize and Purify a Detergent-Sensitive Membrane Protein Assembly

The peptidisc membrane mimetic enables global reconstitution of the bacterial membrane proteome into water-soluble detergent-free particles, termed peptidisc libraries. We present here a method that combines peptidisc libraries and chromosomal-level gene tagging technology with affinity purification and mass spectrometry (AP/MS) to stabilize and identify fragile membrane protein complexes that exist at native expression levels. This method circumvents common artifacts caused by bait protein overproduction and protein complex dissociation due to lengthy exposure to detergents during protein isolation. Using the E. coli Sec system as a case study, we identify an expanded version of the translocon, termed the HMD complex, consisting of 9 different integral membrane subunits. This complex is stable in peptidiscs but dissociates in detergent. Guided by this native-level proteomic information, we design and validate a procedure that enables purification of the HMD complex with minimal protein dissociation. These results highlight the utility of peptidiscs and AP/MS to discover and stabilize fragile membrane protein assemblies.

biochemistry↗

bioRxiv2022

Substrate topology and cognate immunity modulate antibacterial toxicity of Tae cell wall hydrolases

Members of the bacterial T6SS amidase effector (Tae) superfamily of toxins are delivered between competing bacteria to degrade cell wall peptidoglycan. Although Taes share a common substrate, they exhibit distinct antimicrobial potency across different competitor species. To investigate the molecular basis governing these differences, we quantitatively defined the functional determinants of Tae1 from Pseudomonas aeruginosa PAO1 using a combination of nuclear magnetic resonance (NMR) and a high-throughput in vivo genetic approach called deep mutational scanning (DMS). As expected, combined analyses confirmed the role of critical residues near the Tae1 catalytic center. Unexpectedly, DMS revealed substantial contributions to enzymatic activity from a much larger, ring-like functional hot spot extending around the entire circumference of the enzyme. Comparative DMS across distinct growth conditions highlighted how functional contribution of different surfaces is highly context-dependent, varying alongside composition of targeted cell walls. These observations suggest that Tae1 engages with the intact cell wall network through a more distributed three-dimensional interaction interface than previously appreciated, providing an explanation for observed differences in antimicrobial potency across divergent Gram-negative competitors. Further binding studies of several Tae1 variants with their cognate immunity protein demonstrate that requirements to maintain protection from Tae activity may be a significant constraint on the mutational landscape of tae1 toxicity in the wild. In total, our work reveals that Tae diversification has likely been shaped by multiple independent pressures to maintain interactions with binding partners that vary across bacterial species and conditions.

biochemistry↗

bioRxiv2022

Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progenitors

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic inflammation and can result in protracted symptoms. Robust systemic inflammation may trigger persistent changes in hematopoietic cells and innate immune memory through epigenetic mechanisms. We reveal that rare circulating hematopoietic stem and progenitor cells (HSPC), enriched from human blood, match the diversity of HSPC in bone marrow, enabling investigation of hematopoiesis and HSPC epigenomics. Following COVID-19, HSPC retain epigenomic alterations that are conveyed, through differentiation, to progeny innate immune cells. Epigenomic changes vary with disease severity, persist for months to a year, and are associated with increased myeloid cell differentiation and inflammatory or antiviral programs. Epigenetic reprogramming of HSPC may underly altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors. One Sentence SummaryTranscriptomic and epigenomic analysis of blood reveal sustained changes in hematopoiesis and innate immunity after COVID-19. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/479588v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1ffe42dorg.highwire.dtl.DTLVardef@dd4868org.highwire.dtl.DTLVardef@1bcae8borg.highwire.dtl.DTLVardef@674e85_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoM{Phi}). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

immunology↗

bioRxiv2022

Cyanopeptides Restriction and Degradation Co-mediate Microbiota Assembly During a Freshwater Cyanobacterial Harmful Algal Bloom (CyanoHAB)

Cyanobacterial harmful algal blooms (CyanoHABs) are globally intensifying and exacerbated by climate change and eutrophication. However, microbiota assembly mechanisms underlying CyanoHABs remain scenario specific and elusive. Especially, cyanopeptides, as a group of bioactive secondary metabolites of cyanobacteria, could affect microbiota assembly and ecosystem function. Here, the trajectory of cyanopeptides were followed and linked to microbiota during Microcystis-dominated CyanoHABs in lake Taihu, China. The most abundant cyanopeptide classes detected included microginin, spumigin, microcystin, nodularin and cyanopeptolin with total MC-LR-equivalent concentrations between 0.23 and 2051.54 ppb, of which cyanotoxins beyond microcystins (e.g., cyanostatin B and nodularin_R etc.) far exceeded reported organismal IC50 and negatively correlated with microbiota diversity, exerting potential collective eco-toxicities stronger than microcystins alone. The microbial communities were differentiated by size fraction and sampling date throughout CyanoHABs, and surprisingly, their variances were better explained by cyanopeptides (19-38%) than nutrients (0-16%). Cyanopeptides restriction (e.g., inhibition) and degradation are first quantitatively verified as the deterministic drivers governing community assembly, with stochastic processes being mediated by interplay between cyanopeptide dynamics and lake microbiota. This study presents an emerging paradigm in which cyanopeptides restriction and degradation co-mediate lake water microbiota assembly, unveiling new insights about the ecotoxicological significance of CyanoHABs to freshwater ecosystems.

ecology↗

bioRxiv2021

dbGSRV: a manually curated database of genetic susceptibility to respiratory virus

Human genetics has been proposed to play an essential role in inter-individual differences in respiratory virus infection occurrence and outcomes. To systematically understand human genetic contributions to respiratory virus infection, we developed the database dbGSRV, a manually curated database that integrated the host genetic susceptibility and severity studies of respiratory viruses scattered over literatures in PubMed. At present, dbGSRV contains 1932 records of genetic association studies relating 1010 unique variants and seven respiratory viruses, manually curated from 168 published articles. Users can access the records by quick searching, batch searching, advanced searching and browsing. Reference information, infection status, population information, mutation information and disease relationship are provided for each record, as well as hyper links to public databases in convenient of users accessing more information. In addition, a visual overview of the topological network relationship between respiratory viruses and associated genes is provided. Therefore, dbGSRV offers a promising avenue to facilitate researchers to dissect human factors in respiratory virus infection, define novel drug targets, conduct risk stratification of population and develop personalized medicine approaches. Database URL: http://www.ehbio.com/dbGSRV/front/

bioinformatics↗

bioRxiv2021

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/470415v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@14625org.highwire.dtl.DTLVardef@1a43372org.highwire.dtl.DTLVardef@12dc0c8org.highwire.dtl.DTLVardef@cbb835_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Microbial consortiums of putative degraders of low-density polyethylene-associated compounds in the ocean

Polyethylene (PE) is one of the most abundant plastics in the ocean. The development of a biofilm on PE in the ocean has been reported, yet whether some of the biofilm-forming organisms can biodegrade this plastic in the environment remains unknown. Via metagenomics analysis, we taxonomically and functionally analysed three biofilm communities using low-density polyethylene (LDPE) as their sole carbon source for two years. Several of the taxa that increased in relative abundance over time were closely related to known degraders of alkane and other hydrocarbons. Alkane degradation has been proposed to be involved in PE degradation, and most of the organisms increasing in relative abundance over time harboured genes encoding proteins essential in alkane degradation, such as the genes alkB and CYP153, encoding an alkane monooxygenase and a cytochrome P450 alkane hydroxylase. Weight loss of PE sheets when incubated with these communities and chemical and electron microscopic analyses provided evidence for alteration of the PE surface over time. Taken together, these results provide evidence for the utilization of LDPE-associated compounds by the prokaryotic communities. This study identifies a group of genes potentially involved in the degradation of the LDPE polymeric structure and/or associated plastic additives in the ocean and describes a phylogenetically diverse community of plastic biofilm-dwelling microbes with the potential of utilizing LDPE-associated compounds as carbon and energy source. ImportanceLow-density polyethylene (LDPE) is one of the most used plastics worldwide and a large portion of it ends up in the ocean. Very little is known about its fate in the ocean and whether it can be biodegraded by microorganisms. By combining 2-year incubations with metagenomics, respiration measurements and LDPE surface analysis, we identified bacteria and associated genes and metabolic pathways potentially involved in LDPE biodegradation. After two years of incubation, two of the microbial communities exhibited a very similar taxonomic composition mediating changes to the LDPE pieces they were incubated with. We provide evidence that there are plastic-biofilm dwelling bacteria in the ocean, that might have the potential to degrade LDPE-associated compounds, and that alkane degradation pathways might be involved.

microbiology↗

bioRxiv2021

T1SEstacker: A tri-layer stacking model effectively predicts bacterial type 1 secreted proteins based on C-terminal non-RTX-motif sequence features

The proteins secreted through type 1 secretion systems often play important roles in pathogenicity of various gram-negative bacteria. However, the type 1 secretion mechanism remains unknown. In this research, we observed the sequence features of RTX proteins, a major class of type 1 secreted substrates. We found striking non-RTX-motif amino acid composition patterns at the C-termini, most typically exemplified by the enriched [FLI][VAI] at the most C-terminal two positions. Machine-learning models, including deep-learning models, were trained using these sequence-based non-RTX-motif features, and further combined into a tri-layer stacking model, T1SEstacker, which predicted the RTX proteins accurately, with a 5-fold cross-validated sensitivity of ~0.89 at the specificity of ~0.94. Besides substrates with RTX motifs, T1SEstacker can also well distinguish non-RTX-motif type 1 secreted proteins, further suggesting their potential existence of common secretion signals. In summary, we made comprehensive sequence analysis on the type 1 secreted RTX proteins, identified common sequence-based features at the C-termini, and developed a stacking model that can predict type 1 secreted proteins accurately.

microbiology↗

bioRxiv2021

G6PD deficiency sensitizes metastasizing melanoma cells to oxidative stress and glutaminolysis

The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To test this, we mutated the substrate binding site of Glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative branch of the pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors but when these tumors spontaneously metastasized the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species (ROS), decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing the production of NADPH through glutaminolysis. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutamine as compared to control melanomas. The oxidative pentose phosphate pathway and compensatory glutaminolysis thus confer layered protection against oxidative stress during metastasis. SignificanceMelanoma metastasis is limited by oxidative stress. Cells that enter the blood experience high levels of ROS and usually die of ferroptosis. We found that melanoma cells become more dependent upon the oxidative branch of the pentose phosphate pathway to manage oxidative stress during metastasis. When pentose phosphate pathway function was disabled by G6PD mutation, the melanoma cells increased their utilization of malic enzyme, fueled by increased consumption of glutamine in the tricarboxylic acid cycle. Melanoma cells thus have redundant and layered protection against oxidative stress.

cancer biology↗

bioRxiv2021

Oxytocinergic modulation of stress-associated amygdala-hippocampus pathways in humans is specially mediated by serotonergic mechanisms

BackgroundThe hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting state fMRI study aimed at determining whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT. MethodsWe employed a randomized placebo-controlled double-blind parallel-group pharmacological fMRI resting state experiment during which n = 112 healthy male participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or the corresponding placebo-control protocols (ATDc) before the administration of intranasal OXT or placebo intranasal spray, respectively. ResultsOXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, while this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via ATD. In the absence of OXT or 5-HT modulation this pathway showed a trend for an association with self-reported stress perception in everyday life. No interactive effects were observed for the right amygdala. ConclusionsTogether, the findings provide first evidence that effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in men.

neuroscience↗

bioRxiv2021

Scrutiny of human lung infection by SARS-CoV-2 and associated human immune responses in humanized mice

There is an urgent need for animal models of COVID-19 to study immunopathogenesis and test therapeutic intervenes. In this study we showed that NSG mice engrafted with human lung (HL) tissue (NSG-L mice) could be infected efficiently by SARS-CoV-2, and that live virus capable of infecting Vero cells was found in the HL grafts and multiple organs from infected NSG-L mice. RNA-seq examination identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, interferon stimulation, and pulmonary fibrosis between HL grafts from infected and control NSG-L mice. Furthermore, when infecting humanized mice with human immune system (HIS) and autologous HL grafts (HISL mice), the mice had bodyweight loss and hemorrhage and immune cell infiltration in HL grafts, which were not observed in immunodeficient NSG-L mice, indicating the development of anti-viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live virus at the later time. These results demonstrate that NSG-L and HISL mice are susceptible to SARS-CoV-2 infection, offering a useful in vivo model for studying SARS-CoV-2 infection and the associated immune response and immunopathology, and testing anti-SARS-CoV-2 therapies.

immunology↗

bioRxiv2021

The endoplasmic reticulum adopts two distinct tubule forms

The endoplasmic reticulum (ER) is a versatile organelle with diverse functions. Through super-resolution microscopy, we show that the peripheral ER in the mammalian cell adopts two distinct forms of tubules. Whereas an ultrathin form, R1, is consistently covered by ER-membrane curvature-promoting proteins, e.g., Rtn4 in the native cell, in the second form, R2, Rtn4 and analogs are arranged into two parallel lines at a conserved separation of [~]105 nm over long ranges. The two tubule forms together account for [~]90% of the total tubule length in the cell, with either one being dominant in different cell types. The R1-R2 dichotomy and the final tubule geometry are both co-regulated by Rtn4 (and analogs) and the ER sheet-maintaining protein Climp63, which respectively define the edge curvature and lumen height of the R2 tubules to generate a ribbon-like structure of well-defined width. Accordingly, the R2 tubule width correlates positively with the Climp63 intralumenal size. The R1 and R2 tubules undergo active remodeling at the second/sub-second time scales as they differently accommodate proteins, with the former effectively excluding ER-luminal proteins and ER-membrane proteins with large intraluminal domains. We thus uncover a dynamic structural dichotomy for ER tubules with intriguing functional implications.

cell biology↗

bioRxiv2021

A new Mendelian Randomization method to estimate causal effects of multivariable brain imaging exposures

The advent of simultaneously collected imaging-genetics data in large study cohorts provides an unprecedented opportunity to assess the causal effect of brain imaging traits on externally measured experimental results (e.g., cognitive tests) by treating genetic variants as instrumental variables. However, classic Mendelian Randomization methods are limited when handling high-throughput imaging traits as exposures to identify causal effects. We propose a new Mendelian Randomization framework to jointly select instrumental variables and imaging exposures, and then estimate the causal effect of multivariable imaging data on the outcome. We validate the proposed method with extensive data analyses and compare it with existing methods. We further apply our method to evaluate the causal effect of white matter microstructure integrity on cognitive function. The findings suggest that our method achieved better performance regarding sensitivity, bias, and false discovery rate compared to individually assessing the causal effect of a single exposure and jointly assessing the causal effect of multiple exposures without dimension reduction. Our application results indicated that WM measures across different tracts have a joint causal effect that significantly impacts the cognitive function among the participants from the UK Biobank.

bioinformatics↗

bioRxiv2021

deCS: A tool for systematic cell type annotations of single-cell RNA sequencing data among human tissues

Single-cell RNA sequencing (scRNA-seq) is revolutionizing the study of complex and dynamic cellular mechanisms. However, cell-type annotation remains a main challenge as it largely relies on a priori knowledge and manual curation, which is cumbersome and less accurate. The increasing number of scRNA-seq data sets, as well as numerous published genetic studies, motivated us to build a comprehensive human cell type reference atlas. Here, we present deCS (decoding Cell type-Specificity), an automatic cell type annotation method augmented by a comprehensive collection of human cell type expression profiles and marker genes. We used deCS to annotate scRNA-seq data from various tissue types and systematically evaluated the annotation accuracy under different conditions, including reference panels, sequencing depth and feature selection strategies. Our results demonstrated that expanding the references is critical for improving annotation accuracy. Compared to many existing state-of-the-art annotation tools, deCS significantly reduced computation time and increased accuracy. deCS can be integrated into the standard scRNA-seq analytical pipeline to enhance cell type annotation. Finally, we demonstrated the broad utility of deCS to identify trait-cell type associations in 51 human complex traits, providing deeper insights into the cellular mechanisms of disease pathogenesis. All documents, including source code, user manual, demo data, and tutorials, are freely available at https://github.com/bsml320/deCS.

bioinformatics↗

bioRxiv2021

Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME

Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contribute to adverse fetal outcomes are sparsely defined. Here, we discovered that ZIKV causes the pyroptosis of placental cells by activating the executor Gasdermin E (GSDME) in vitro and in vivo. Mechanistically, caspase-8 undergoes activation upon the recognition of 5 untranslated region of viral RNA by RIG-I, followed by the stimulation of caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which could be employed for developing new therapies for ZIKV-associated diseases. Significance statementSeveral studies have elucidated the link between ZIKV infection and congenital ZIKV syndroms (CZS), but the pathogenesis yet needs further study. Here, we reported a novel pathogenic mechanism of ZIKV which leads to pyroptosis of placental cells through activating the pyroptotic executor GSDME, rather than GSDMD. Upon ZIKV infection, GSDME-mediated pyroptosis damages the structure and function of the placenta, thereby affecting the development of the fetus and contributing to the adverse fetal outcomes. Our study highlights the importance of pyroptotic executor GSDME in regulate ZIKV pathogenicity and further confirms that placental injury caused by ZIKV infection is a key factor for CZS.

microbiology↗