Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 685 records · Page 38Linked to original sources

bioRxiv2022

TimiGP: inferring inter-cell functional interactions and clinical values in the tumor immune microenvironment through gene pairs

Determining how immune cells functionally interact in the tumor microenvironment and identifying their biological roles and clinical values are critical for understanding cancer progression and developing new therapeutic strategies. Here we introduce TimiGP, a computational method to infer inter-cell functional interaction networks and annotate the corresponding prognostic effect from bulk gene expression and survival statistics data. When applied to metastatic melanoma, TimiGP overcomes the prognostic bias caused by immune co-infiltration and identifies the prognostic value of immune cells consistent with their anti- or pro-tumor roles. It reveals the functional interaction network in which the interaction X[->]Y indicates a more positive impact of cell X than Y on survival. This network provides immunological insights to facilitate the development of prognostic models, as evidenced by our computational-friendly, biologically interpretable, independently validated models. By leveraging single-cell RNA-seq data for specific immune cell subsets, TimiGP has the flexibility to delineate the tumor microenvironment at different resolutions and is readily applicable to a wide range of cancer types.

bioinformatics↗

bioRxiv2022

The effect of context congruency on fMRI repetition suppression for objects

The recognition of objects is strongly facilitated when they are presented in the context of other objects (Biederman, 1972). Such contexts facilitate perception and induce expectations of context-congruent objects (Trapp & Bar, 2015). The neural mechanisms underlying these facilitatory effects of context on object processing, however, are not yet fully understood. In the present study, we investigate how context-induced expectations affect subsequent object processing. We used functional magnetic resonance imaging and measured repetition suppression, a proxy for prediction error processing, for pairs of alternating or repeated object images, preceded by context-congruent, context-incongruent or neutral cues. We found a stronger repetition suppression in congruent as compared to incongruent or neutral cues in the object sensitive lateral occipital cortex. Interestingly, this effect was driven by enhanced responses to alternating stimulus pairs in the congruent contexts. In addition, in the congruency condition, we discovered significant functional connectivity between object-responsive and frontal cortical regions, as well as between object-responsive regions and the fusiform gyrus. Our findings unravel the neural mechanisms underlying context facilitation.

neuroscience↗

bioRxiv2022

'Simple Tidy GeneCoEx': a gene co-expression analysis workflow powered by tidyverse and graph-based clustering in R

Gene co-expression analysis is an effective method to detect groups (or modules) of co-expressed genes that display similar expression patterns, which may function in the same biological processes. Here, we present Simple Tidy GeneCoEx, a gene co-expression analysis workflow written in the R programming language. The workflow is highly customizable across multiple stages of the pipeline including gene selection, edge selection, clustering resolution, and data visualization. Powered by the tidyverse package ecosystem and network analysis functions provided by the igraph package, the workflow detects gene co-expression modules whose members are highly interconnected. Step-by-step instructions with two use case examples as well as source code are available at https://github.com/cxli233/SimpleTidy_GeneCoEx. Core IdeasO_LIAn R-based workflow that performs gene co-expression analysis was developed. C_LIO_LIThe workflow is based on tidyverse packages and graph theory. C_LIO_LIThe workflow is highly customizable, detects tight gene co-expression modules, and generates publication quality figures. C_LIO_LITwo plant gene expression datasets were used to benchmark the workflow. C_LI

plant biology↗

bioRxiv2022

Disruption of OsLAT5 is sufficient to endow rice tolerance to dihydropyridine herbicides at commercial application concentrations

Breeding non-selective herbicide-resistant crops is important constituent of weed management system in modern rice production. Non-selective dihydropyridine herbicide shares transporters with polyamine (PA), making construction of a dihydropyridine herbicide-resistant rice line possible by inactivating the PA transporter function via gene editing. Success depends on understanding substrate selection for homologues in the PA transporter family and amino acid sites that play critical roles. Here, OsLAT1 was mainly responsible for root uptake and root-to-shoot transport; whereas, OsLAT5 was more responsible for intracellular transport to chloroplasts. The oslat5 disruption line tolerated relevant concentrations, while oslat1 did not. Compared to GY11 wild type, plant height, 1000-grain weight, and spermidine, spermine, and putrescine content changes occurred in GY11-oslat5 lines, implying involvement of OsLAT5 in yield and quality regulation. OsLAT5P44F, P44Y and P44R showed declined dihydropyridine herbicide uptake but no spermidine and putrescine transport competence disruption in yeast, providing a candidate site for precisely editing in breeding a dihydropyridine herbicide-resistant rice cultivar without impairing rice yield and grain quality.

plant biology↗

bioRxiv2022

TCR_Explore: a novel webtool for T cell receptor repertoire analysis

T cells expressing either alpha-beta or gamma-delta T cell receptors (TCR) are critical sentinels of the adaptive immune system, with receptor diversity being essential for protective immunity against a broad array of pathogens and agents. Programs available to profile TCR clonotypic signatures can be limiting for users with no coding expertise. Current analytical pipelines can be inefficient due to manual processing steps, open to data transcription errors and have multiple analytical tools with unique inputs that require coding expertise. Here we present a bespoke webtool designed for users irrespective of coding expertise, coined TCR_Explore, incorporating automated quality control steps that generates a single output file for creation of flexible and publication ready figures. TCR_Explore will elevate a users capacity to undertake in-depth TCR repertoire analysis of both new and pre-existing datasets for identification of T cell clonotypes associated with health and disease. The web application is located at https://tcr-explore.erc.monash.edu for users to interactively explore TCR repertoire datasets. Key PointsO_LIBespoke program for non-specialists in computerised methodologies for deep exploration of TCR repertoire analysis C_LIO_LIAutomated QC and analysis pipelines for Sanger based TCR sequencing coupled with immunophenotyping, with the capacity for integration of other sequencing platform outputs C_LIO_LIAutomated summary processes to aid data visualisation and generation of publication-ready graphical displays C_LI

bioinformatics↗

bioRxiv2022

Nuclei isolation protocol from diverse angiosperm species

The ability to generate intact nuclei is crucial to the success of a variety of genomics experiments, such as Assay for Transposase-Accessible Chromatin using sequencing (ATAC- seq), Cleavage Under Targets and Tagmentation (CUT&Tag), and nuclei-based single cell sequencing (e.g., single nuclei ATAC-seq and single nuclei RNA-seq). For plants, the presence of the cell wall presents significant challenges in the isolation of nuclei from tissues. Here, we report an optimized nuclei isolation protocol that can be adapted for diverse angiosperm species, including maize, soybean, tomato, potato, and wheat, starting from fresh or frozen tissues. Nuclei release is achieved through chopping tissue on ice, where a key parameter affecting nuclei integrity is the concentration of detergent TritonX-100 in the nuclei isolation buffer. The method is simple, quick, and largely centrifugation-free, in which debris is removed by serial filtration. Initial nuclei release and filtration can be performed within 20 min. Fluorescence activated nuclei sorting is then used for final nuclei purification to remove other organelles such as plastids. The protocol uses 500 mg or less plant tissue as input and typically yields at least 100,000 - 200,000 purified nuclei per sample, a common input amount for downstream experiments. Throughout the protocol, we provide guidelines for optimization if performing nuclei isolation from a given species and tissue for the first time.

plant biology↗

bioRxiv2022

Induction of Autophagy Prevents Mutant SOD1G93A Related Neurotoxicity in Experimental Models of Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting from the progressive loss of both upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, there are only two drugs, Riluzole (Rilutek) and Edaravone (Radicava), approved by FDA for ALS treatment. These two drugs are very expensive with only a few months of life extension. So far, there is no cure for ALS. Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS. The disturbance in protein homeostasis may contribute to the onset and progression of ALS. Autophagy plays an important role in degrading misfolded proteins, thereby preventing their aggregation. Pharmacological manipulation of autophagy has been proposed as a new therapeutic approach for treating ALS. IADB, a novel indole alkaloid derivative, has been reported to exert mitochondrial protection and cardioprotection through its autophagy-modulating potential. Our present study attempted to examine whether IADB has therapeutic potential in SOD1G93A-associated experimental models of ALS. We found that IADB could promote the clearance of SOD1G93A aggregates and reduce the overproduction of mitochondrial reactive oxygen species (mtROS) in motor neuron-like NSC-34 cells transfected with SOD1G93A. We further examined the IADB in a SOD1-G93A mouse model of ALS. Administration of IADB started at the age of 55 days until the end stage of the disease. IADB treatment significantly increased LC3-II levels and decreased human SOD1 levels and p62 expression in the spinal cords of SOD1G93A mice, suggesting that IADB treatment could induce autophagy activation and promote clearance of mutant SOD1 aggregates in this mouse model of ALS. Moreover, IADB treatment could alleviate the activation of microglia and astrocytes and reduce mitochondrial oxidative damage in the spinal cord of SOD1G93A mice. Finally, we demonstrated that IADB treatment could improve motor performance and delay the onset and progression of the disease in a mouse model of ALS. The neuroprotective effects of IADB may mainly originate from its autophagy-promoting property.

neuroscience↗

bioRxiv2022

Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders

The prefrontal cortex (PFC) has been implicated as a key brain region responsible for age-related cognitive decline. Little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods with integrated analyses to determine PFC molecular changes in healthy female primates. We quantified PFC changes associated with healthy aging in female baboons by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis (WGCNA) to integrate data and treat age as a continuous variable, revealed highly interconnected known and novel pathways associated with PFC aging. We found GABA tissue content associated with these signaling pathways, providing one potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.

systems biology↗

bioRxiv2022

Tomato geranylgeranyl diphosphate synthase isoform 1 specifically interacts with phytoene synthase isoform 3 to produce strigolactones in tomato roots.

O_LICarotenoids are photoprotectant pigments and precursors of the hormones abscisic acid (ABA) and strigolactones (SL). Carotenoids are produced in plastids from geranylgeranyl diphosphate (GGPP), which is diverted to the carotenoid pathway by phytoene synthase (PSY). In tomato (Solanum lycopersicum), 3 genes encode plastid-targeted GGPP synthases (SlG1 to 3) and 3 genes encode PSY isoforms (PSY1 to 3). C_LIO_LIHere we investigated the function of SlG1 by generating loss-of-function lines and combining their metabolic and physiological phenotypes with gene co-expression and co-immunoprecipitation analyses. C_LIO_LILeaves and fruits of slg1 lines showed a wild-type phenotype in terms of isoprenoid accumulation, photosynthesis and development. Consistently, SlG1 is co-expressed with PSY3 and other genes involved in the production of carotenoids and SL (but not ABA) only in roots. SlG1 was also found to physically interact with the root-specific PSY3 isoform (and not with PSY1 and PSY2). Root SL (but not ABA) levels were reduced in slg1 lines. C_LIO_LIOur results confirm a specific role of SlG1 in SL production in combination with PSY3. This role appears to be restricted to roots as slg1 plants do not exhibit the shoot phenotype displayed by other SL-deficient mutants. C_LI

plant biology↗

bioRxiv2022

The protist ubiquitin ligase effector PbE3-2 targets RD21A to impede plant immunity

Clubroot caused by the soil-borne protist pathogen Plasmodiophora brassicae is one of the most devastating diseases of Brassica oil and vegetable crops worldwide. Understanding the pathogen infection strategy is crucial for the development of disease control. However, the molecular mechanism by which this pathogen promotes infection remains largely unknown. Here, we identified a P. brassicae-secreted effector PbE3-2 that impedes plant immunity by ubiquitinating the immune regulator RD21A for degradation. Overexpression of PbE3-2 in Arabidopsis thaliana resulted in higher susceptibility to P. brassicae and decreases in chitin-triggered reactive oxygen species burst and expression of marker genes in salicylic acid signaling. PbE3-2 interacted with and ubiquitinated RD21A in vitro and in vivo. Mutant plants deficient in RD21A exhibited similar susceptibility and compromsied immune responses as in PbE3-2 overexpression plants. These results suggest that P. brassicae promotes clubroot disease through RD21A degradation mediated by the effector PbE3-2. As PbE3-2 is widely conserved across different P. brassicae pathotypes, the degradation of RD21A by PbE3-2 might be a prevalent infection strategy in this pathogen.

microbiology↗

bioRxiv2022

Sex-dimorphic neuroprotective effect of CD163 in an alpha-synuclein mouse model Of Parkinson's disease

Alpha-synuclein (-syn) aggregation and immune activation represent hallmark pathological events in Parkinsons disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in the PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine -syn pre-formed fibrils (PFF) in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to -syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and -syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a novel, sex-dimorphic neuroprotective role for CD163 during -syn-induced neurodegeneration.

neuroscience↗

bioRxiv2022

SituSeq: An offline protocol for rapid and remote Nanopore amplicon sequence analysis

Microbiome analysis through 16S rRNA gene sequencing is a crucial tool for understanding the microbial ecology of any habitat or ecosystem. However, workflows require large equipment, stable internet, and extensive computing power such that most of the work is performed far away from sample collection in both space and time. Performing amplicon sequencing and analysis at sample collection would have positive implications in many instances including remote fieldwork and point-of-care medical diagnoses. Here we present SituSeq, an offline and portable workflow for the sequencing and analysis of 16S rRNA gene amplicons using the Nanopore MinION and a standard laptop computer. SituSeq was validated using the same environmental DNA to sequence Nanopore 16S rRNA gene amplicons, Illumina 16S rRNA gene amplicons, and Illumina metagenomes. Comparisons revealed consistent community composition, ecological trends, and sequence identity across platforms. Correlation between the abundance of phyla in Illumina and Nanopore data sets was high (Pearsons r = 0.9), and over 70% of Illumina 16S rRNA gene sequences matched a Nanopore sequence with greater than 97% sequence identity. On board a research vessel on the open ocean, SituSeq was used to analyze amplicon sequences from deep sea sediments less than two hours after sequencing, and eight hours after sample collection. The rapidly available results informed decisions about subsequent sampling in near real-time while the offshore expedition was still underway. SituSeq is a portable and robust workflow that helps to bring the power of microbial genomics and diagnostics to many more researchers and situations.

microbiology↗

bioRxiv2022

Flexible IrOx Neural Electrode for Mouse Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is being actively explored as a treatment for multiple conditions as part of bioelectronic medicine research. Reliable and safe VNS in mouse models is a critical need for understanding mechanisms of these. We report on the development and evaluation of a microfabricated cuff electrode (MouseFlex) constructed of polyimide (PI) and with iridium oxide (IrOx) electrodes that is thermoformed to 86 {micro}m {+/-} 12 {micro}m radius to interface the mouse cervical vagus nerve (r {approx} 50 {micro}m). Innovative bench-top methods were used to evaluated the stimulation stability and electrochemical properties of electrodes. Our aggressive stimulation stability (Stim-Stab) test utilized 1 billion pulses at a 1000 Hz with a current density of 6.28 A/cm2 (1.51 mC/cm2/phase) to evaluate electrode lifetimes, and all electrodes remained functional. We also investigated the effects of thermoforming on their impedance, charge storage capacity (CSC), and charge injection capacity (CIC). The modest changes in electrochemical properties indicate that the thermoforming process was well tolerated. Thermoformed electrode safety and efficacy were evaluated in-vivo by performing acute VNS in mice and monitoring their heart and respiration rate as biomarkers. Their electrochemical properties were also measured before, during and after VNS. Bradycardia and bradypnea were reliably induced at stimulation currents of 100 to 200 {micro}A, well below the in-vivo CIC of ~1250 {micro}A (~0.5 mC/cm2), supporting their safety and efficacy. The electrode impedance increased and CIC decreased during in-vivo use, but largely reversed these changes in in-vitro testing after enzymatic cleaning, supporting their tolerance for surgical use.

bioengineering↗

bioRxiv2022

Bacterial anomalies in seabed sediments associated with deep water hydrocarbon seepage

Deep sea hydrocarbon seep detection relies predominantly on geochemical analyses of seabed marine sediment cores to identify the presence of gas or oil. The presence of seeping hydrocarbons in these locations alters resident microbial community structure, leading to culture-based biodegradation assays as a complement to geochemical tools for seep detection. Biodiversity surveys of microbial communities can offer a similar proxy for seeping hydrocarbons, but this strategy has not been extensively investigated in deep water settings. In this study, 16S rRNA gene sequencing of bacterial communities was performed on sediment cores obtained in >2500 m water depth at 43 different locations in the NW Atlantic Ocean. Core samples from as deep as 10 metres below seafloor (mbsf) were assessed for gas composition, gas isotopes and liquid hydrocarbons. Over 650 bacterial 16S rRNA gene amplicon libraries were constructed from different sediment depths at these locations. Select sites showed strong evidence for the presence of thermogenic or biogenic hydrocarbons such that bacterial population analyses revealed significant differences between hydrocarbon seep and non-seep locations. Specific bacterial indicators were associated with different sediment depth intervals. Caldatribacteriota and Campilobacterota OTUs were observed in high relative sequence abundance in hydrocarbon seep sediments, particularly in the 20-50 cmbsf interval. Furthermore, these groups were differentially abundant between sites with thermogenic and biogenic hydrocarbons. The patterns revealed here suggest that microbial screening has the potential to play a key role in hydrocarbon seep detection and characterisation in remote deep-sea environments.

microbiology↗

bioRxiv2022

EARLY FLOWERING 3 interactions with PHYTOCHROME B and PHOTOPERIOD1 are critical for the photoperiodic regulation of wheat heading time

The photoperiodic response is critical for plants to adjust their reproductive phase to the most favorable season. Wheat heads earlier under long days (LD) than under short days (SD) and this difference is mainly regulated by the PHOTOPERIOD1 (PPD1) gene. Tetraploid wheat plants carrying the Ppd-A1a allele with a large deletion in the promoter head earlier under SD than plants carrying the wildtype Ppd-A1b allele with an intact promoter. Phytochromes PHYB and PHYC are necessary for the light activation of PPD1, and mutations in either of these genes result in the downregulation of PPD1 and very late heading time. We show here that both effects are reverted when the phyB mutant is combined with loss-of-function mutations in EARLY FLOWERING 3 (ELF3), a component of the Evening Complex (EC) in the circadian clock. We also show that the wheat ELF3 protein interacts with PHYB and PHYC, is rapidly modified by light, and binds to the PPD1 promoter in planta (likely as part of the EC). Deletion of the ELF3 binding region in the Ppd-A1a promoter results in its upregulation at dawn, similar to PPD1 alleles with intact promoters in the elf3 mutant background. The upregulation of PPD1 is correlated with the upregulation of the florigen gene FLOWERING LOCUS T1 (FT1) and early heading time. Loss-of-function mutations in ppd1 result in the downregulation of FT1 and delayed heading, even when combined with the elf3 mutation. Taken together, these results indicate that ELF3 operates downstream of PHYB as a direct transcriptional repressor of PPD1, and that this repression is relaxed both by light and by the deletion of the ELF3 binding region in the Ppd-A1a promoter. In summary, the regulation of the light mediated activation of PPD1 by ELF3 is critical for the photoperiodic regulation of wheat heading time. Author SummaryThe coordination of reproductive development with the optimal season for seed production is critical to maximize grain yield in crop species. Plants can perceive the length of the day or night (photoperiod) and use this information to anticipate seasonal changes. In most eudicot plants, CONSTANS plays a central role in the perception of photoperiod, but in wheat the main photoperiod gene is PHOROPERIOD1 (PPD1). In this study, we show that the clock gene EARLY FLOWERING 3 (ELF3) regulates the phytochrome-mediated light activation of PPD1. Loss-of-function mutations in ELF3 result in the upregulation of PPD1 at and dawn, and in early heading under both long and short days, even in the absence of PHYB. A deletion in the PPD1 promoter including an ELF3 binding region also results in earlier heading under short days, indicating that ELF3 acts as a direct transcriptional repressor of PPD1. This study shows that ELF3 plays a critical role in the wheat photoperiod pathway by regulating the light signal between the phytochromes and PPD1. ELF3 provides an additional entry point to engineer heading time in wheat, an important trait for the development of better adapted varieties to a changing environment.

plant biology↗

bioRxiv2022

Molecular Recognition of Itching Neuropeptides by Bombesin Receptors.

Neuromedin B (NMB) and gastrin-releasing peptide (GRP), two bombesin analogs, are endogenous itch-specific neuropeptides that induce histaminergic and nonhistaminergic itch, respectively. Their functions are mediated by two G protein-coupled bombesin receptors, NMBR and GRPR. Here we present cryo-electron microscopy(cryo-EM) structures of G protein coupled NMBR and GRPR bound to NMB and GRP, respectively. The structures reveal that both bombesin receptors contain an extended and deep pocket to adopt NMB and GRP, with the conserved C-terminal motif of GH(F/L)M from both peptides to contact the toggle switch residues for the receptor activation. Together with mutational and functional data, our structures reveal the mechanism of ligand selectivity and specific activation of the bombesin receptors. These findings also pave the way to facilitate rational design of therapies targeting bombesin receptors for the treatment of pruritus.

biophysics↗

bioRxiv2022

DeepAIR: a deep-learning framework for effective integration of sequence and 3D structure to enable adaptive immune receptor analysis

Structural docking between the adaptive immune receptors (AIRs), including T cell receptors (TCRs) and B cell receptors (BCRs), and their cognate antigens is one of the most fundamental processes in adaptive immunity. However, current methods for predicting AIR-antigen binding largely rely on sequence-derived features of AIRs, omitting the structure features that are essential for binding affinity. In this study, we present a deep-learning framework, termed DeepAIR, for the accurate prediction of AIR-antigen binding by integrating both sequence and structure features of AIRs. DeepAIR consists of three feature encoders (a trainable-embedding-layer-based gene encoder, a transformer-based sequence encoder, and a pre-trained AlphaFold2-based structure encoder), a gating-based attention mechanism to extract important features, and a tensor fusion mechanism to integrate obtained features. We train and evaluate DeepAIR on three downstream prediction tasks, including the prediction of AIR-antigen binding affinity, the prediction of AIR-antigen binding reactivity, and the classification of the immune repertoire. On five representative datasets, DeepAIR shows outstanding prediction performance in terms of AUC (area under the ROC curve) in predicting the binding reactivity to various antigens, as well as the classification of immune repertoire for nasopharyngeal carcinoma (NPC) and inflammatory bowel disease (IBD). DeepAIR is freely available for academic purposes at https://github.com/TencentAILabHealthcare/DeepAIR. We anticipate that DeepAIR can serve as a useful tool for characterizing and profiling antigen binding AIRs, thereby informing the design of personalized immunotherapy. HighlightsO_LIIntegrating predicted AIR structures using AlphaFold2 significantly improves the prediction accuracy of the binding reactivity between AIRs and antigens. C_LIO_LIDeepAIR is featured by a novel deep learning architecture that leverages both the gating-based attention mechanism and tensor fusion mechanism to effectively extract and integrate informative features from three feature encoders, including a trainable embedding-layer-based gene encoder, a transformer-based sequence encoder, and a pre-trained AlphaFold2-based structure encoder. C_LIO_LIDeepAIR is implemented as a biologically interpretable deep learning framework that highlights the key residues in both and {beta} chains that are critical for predicting the AIR-antigen binding. C_LI

immunology↗

bioRxiv2022

Inhibition of CHK2 dependent DNA damage response suppresses Zika virus infection through a STING dependent mechanism

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes neurological disorders and microcephaly. Recent research has shown that ZIKV causes cell cycle arrest and DNA damage response in neuronal progenitor cells that potentially leads to congenital neurodevelopmental defects. However, the specific role of regulators that control DNA damage response to ZIKV infection and the related mechanisms remain largely unknown. Here through both in vitro and in vivo studies, we observe that ZIKV induces DNA damage response in both human cell line and mouse embryo. When CHK2 dependent DNA damage response pathway is inhibited by a small molecule inhibitor or genetic deletion, ZIKV production is reduced and the embryonic developmental defects are rescued. Furthermore, we demonstrate that in ZIKV infected Chk2-/- mice, the reduced viral load correlates with elevated antiviral innate immune response which is found to be dependent on the STING signaling pathway. Collectively, our study reveals a specific role of CHK2 for ZIKV infection and pathogenesis, demonstrating a mechanism that inhibition of the CHK2 axis suppresses ZIKV infection through the STING-dependent antiviral pathway, thus providing a new therapeutic strategy against ZIKV. These findings also suggest the intriguing possibility that ZIKV evolved to orchestrate DNA damage response factors to create a beneficial environment for its infection in the host cells.

immunology↗