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Zhao, W.

Publications and source records attributed to Zhao, W..

At least 127 records · Page 7Linked to original sources

UltimateSynth: MRI Physics for Pan-Contrast AI

Magnetic resonance imaging (MRI) is commonly used in healthcare for its ability to generate diverse tissue contrasts without ionizing radiation. However, this flexibility complicates downstream analysis, as computational tools are often tailored to specific types of MRI and lack generalizability across the full spectrum of scans used in healthcare. Here, we introduce a versatile framework for the development and validation of AI models that can robustly process and analyze the full spectrum of scans achievable with MRI, enabling model deployment across scanner models, scan sequences, and age groups. Core to our framework is UltimateSynth, a technology that combines tissue physiology and MR physics in synthesizing realistic images across a comprehensive range of meaningful contrasts. This pan-contrast capability bolsters the AI development life cycle through efficient data labeling, generalizable model training, and thorough performance benchmarking. We showcase the effectiveness of UltimateSynth by training an off-the-shelf U-Net to generalize anatomical segmentation across any MR contrast. The U-Net yields highly robust tissue volume estimates, with variability under 4% across 150,000 unique-contrast images, 3.8% across 2,000+ low-field 0.3T scans, and 3.5% across 8,000+ images spanning the human lifespan from ages 0 to 100.

bioinformatics↗

Lineage-associated Human Divergently-Paired Genes (DPGs) Exhibit Regulatory Characteristics and Evolutionary Trends

Divergently-paired genes (DPGs) represent one of the minimal co-transcriptional units (the rest include tandemly- and convergently-paired genes) of clustered genes; the former and the latter constitute greater than 10% and 75% of the total human genes, respectively. Our previous studies have shown that vertebrate DPGs are more conserved, both organizationally and functionally than invertebrates. Three critical questions remain to be addressed: (1) what are the conserved DPGs over vertebrate lineages, especially among mammals and primates? (2) being bidirectionally transcribed, to what extent do DPGs share their promoter sequences and how mechanistically and stringently are their co-expression regulated within the shared inter-TSS (transcription start site) sequence space? and (3) based on the recently released high-quality human genome assemblies, how do human-associated DPGs distribute over selected primate lineages and what are their possible functional consequences biologically? Our study begins by identifying 1399 human DPGs (12% of all human protein-coding genes), and presents findings from this analysis. First, 1136, 1118, 925, and 830 human DPGs are shared genetically with primates, mammals, avians, and fish, respectively. DPGs are not only functionally enriched toward direct protein-DNA interactions and cell cycle synchronization but also exhibit obvious lineage association, narrow in principle toward synchronization of certain core molecular mechanisms and cellular processes. Second, their inter-TSS distances and expression variables affect both co-expression strength and disparity between the two genes. Finally, our results based on a comparison among the primate DPGs reveal that the human-associated DPGs exhibit intensive diversification in co-expression, duplication, and definite involvement in neural development. Within humans, 55 and 357 DPGs are associated to the Chinese (YAO) and the European (CHM13) assemblies, respectively. Our results offer novel insights into comprehending the structure-function selection of gene clusters over evolutionary time scales, as well as a deeper understanding of the regulatory characteristics of co-expressed neighboring genes.

genomics↗

A CRISPR/SpCas9M-reporting system for efficient and rapid genome editing in Caulobacter crescentus

As members of the -proteobacteria group, Caulobacter crescentus and its relatives are known for their asymmetric life cycle and comprehensive applications in gene delivery, agricultural biotechnology, and the production of high-value compounds. However, genetic manipulations of these bacteria are often time-consuming and labor-intensive due to the lack of efficient genome editing tools. Here, we report a practical CRISPR/SpCas9M-reporting system that overcomes the limitations of SpCas9 expression, enabling efficient, markerless, and rapid genome editing in C. crescentus. As a demonstration, we successfully knocked out two genes encoding the scaffold proteins, achieving apparent editing efficiencies up to 80%. Key components, including the Cas protein, Cas inducer, sgRNA, homologous arms, and reporter, were systematically analyzed and optimized to enhance the editing efficiency or decrease the cell lethality. A nearly zero off-target ratio was observed after the curing of the editor plasmid in editing strains. Furthermore, we applied the CRISPR/SpCas9M-reporting system to two C. crescentus relatives, Agrobacterium fabrum and Sinorhizobium meliloti, establishing it as an efficient and reliable editing strategy. We anticipate that this system could be applied to other hard-to-edit organisms, accelerating both basic and applied research in -proteobacteria.

bioengineering↗

Multi-omics analysis of the mechanism of alfalfa and wheat-induced rumen flatulence in Xizang sheep

This study induced a rumen flatulence model in Xizang sheep using alfalfa (HRF) and wheat grass (MRF) to explore related mechanisms. The pH of HRF and MRF groups was lower than the natural grass group. SCFA concentrations varied in different groups. Microbial analysis showed HRF and MRF groups had lower alpha and beta diversity and different compositions. Transcriptome analysis found different numbers of differentially expressed genes in each group. Spearmans correlation analysis indicated Butyrivibrio was related to GLRX and DUOX2, and Quinella to several genes.

microbiology↗

Epigenetic study of the long-term effects of Gulf War illness

Gulf war illness is a chronic multisymptom disorder that affects as many as many as 25-35% of the military personnel who were sent to the Persian Gulf war in 1991. The illness has many debilitating symptoms, including cognitive problems, gastrointestinal symptoms, and musculoskeletal pain. Those so afflicted have been sick for more than 30 years and, therefore, it has become imperative to understand the etiology and then produce treatments to ease the symptoms. We hypothesized that the length of the disease was reflected in epigenetic modification of possibly several genes related to the symptoms. We subjected male and female mice from 11 BXD strains to combined corticosterone and the sarin surrogate, diisopropylfluorophosphate, to emulate the physiological stress of war and the potential exposures to organophosphate pesticides and nerve agent in theater. Three hundred days after treatment, we analyzed the animals DNA for genome-wide methylation by MBD-seq. The analysis revealed 20 methylated genes, notably Eif2B5, that regulates myelin production. Loss of myelin with accompanying musculoskeletal pain is a major symptom of Gulf War illness. Our work demonstrates multiple genes were methylated by exposure to OPs and glucocorticoids. These genes point to biochemical mechanisms that may be targets for therapeutic intervention.

pharmacology and toxicology↗

TRAIT: A Comprehensive Database for T-cell Receptor-Antigen Interactions

Comprehensive and integrated resources on interactions between T-cell receptors and antigens are still lacking for adoptive T-cell-based immunotherapies, highlighting a significant gap that must be addressed to fully comprehend the mechanisms of antigen recognition by T-cells. In this study, we present TRAIT, a comprehensive database that profiles the interactions between T-cell receptors (TCRs) and antigens. TRAIT stands out due to its comprehensive description of TCR-antigen interactions by integrating sequences, structures and affinities. It provides nearly 8 million experimentally validated TCR-antigen pairs, resulting in an exhaustive landscape of antigen-specific TCRs. Notably, TRAIT emphasizes single-cell omics as a major reliable data source for TCR-antigen interactions and includes millions of reliable non-interactive TCRs. Additionally, it thoroughly demonstrates the interactions between mutations of TCRs and antigens, thereby benefiting affinity maturation of engineered TCRs as well as vaccine design. TCRs on clinical trials were innovatively provided. With the significant efforts made towards elucidating the complex interactions between TCRs and antigens, TRAIT is expected to ultimately contribute superior algorithms and substantial advancements in the field of T-cell-based immunotherapies. TRAIT is freely accessible at https://pgx.zju.edu.cn/traitdb.

immunology↗

Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism

Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by {beta}-glucan. ATAC-seq and RNA-seq analysis reveals that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF and NF-{kappa}B pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of {beta}-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM level through mTOR-FOXO3-GNMT axis.

immunology↗

KLF7-Regulated ITGA2 as a Therapeutic Target for Inhibiting Oral Cancer Stem Cells

Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. When bound to its ECM ligand, type I collagen, ITGA2 activates several stemness-related pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, which inhibits the ITGA2-collagen interaction, showed a synergistic anti-tumor effect when combined with cisplatin in both in vitro and xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy. Highlights1) KLF7 as a key molecule in maintaining oral cancer stemness. 2) ITGA2as a key downstream gene regulated by KLF7 in the maintenance of stemness. 3) ITGA2 interacts with extracellular matrix type I collagen, activating stemness-related pathways and promoting YAP1 nuclear translocation to sustain OCSCs. 4) ITGA2 as a novel anti-CSC target, providing a new strategy to overcome OSCC drug resistance.

cancer biology↗

Oral Boldine Administration Attenuates Glia Activation and Prevents Neuropathic Pain in a Murine Spared Nerve Injury Model

BackgroundChronic pain is present in about 20% of the population and is a major burden to the health care system. About 30-40% of these patients report neuropathic pain. Neuropathic pain is defined as pain caused by injury or disease of the somatosensory nervous system. Current available treatments for neuropathic pain have limited efficacy and substantial side effects. MethodsTo address the need for more effective and safer treatments for neuropathic pain, this study aimed to test whether boldine, a naturally occurring alkaloid, could attenuate neuropathic pain in a murine model of spared nerve injury (SNI). Von Frey filament test, hot/cold plate test and dynamic weight bearing test were used to assess pain phenotypes following SNI. ResultsWe found that boldine inhibited the lipopolysaccharide-induced overexpression of inflammatory markers in BV-2 microglial cells. Oral administration of boldine at 50 mg/kg body weight/day resulted in significant reduction of SNI-induced mechanical and thermal hypersensitivity. Boldine also corrected SNI-induced weight bearing deficits, which are an indication of spontaneous pain. Boldine significantly inhibited SNI-induced peripheral inflammation as indicated by reduced levels of inflammatory cytokines/chemokines in the serum. Immunofluorescence studies revealed that boldine reduced the number of reactive astrocytes and inhibited microglia activation in lumbar spinal cord. ConclusionOur findings suggest that boldine may be a promising therapeutic candidate for the treatment of neuropathic pain, possibly through inhibition of glia activation and neuroinflammation.

neuroscience↗

GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18

Neutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limited in vitro analysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity against Aspergillus fumigatus. GATA1 knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and more readily execute neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal {beta}-glucan, including an upregulation of the pentose phosphate pathway (PPP), similar to primary human neutrophils in vitro. Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to kill A. fumigatus but is not necessary for the upregulation of PPP. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response. Author SummaryNeutrophils are important first responders to fungal infections, and understanding their antifungal functions is essential to better elucidating disease dynamics. Primary human neutrophils are short lived and do not permit genetic manipulation, limiting their use to study neutrophil-fungal interactions in vitro. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils for in vitro analyses. In this report we show that GATA1-deficient iPSCs generate neutrophils (iNeutrophils) that are more mature than wild-type iNeutrophils and display increased antifungal activity against the human fungal pathogen Aspergillus fumigatus. We also show that GATA1-deficient iNeutrophils have increased expression of antifungal receptors than wild-type cells and shift their metabolism and execute neutrophil antifungal functions at levels comparable to primary human neutrophils. Deletion of the integrin CD18 blocks the ability of GATA1-deficient iNeutrophils to kill and control the growth of A. fumigatus, demonstrating an important role for this integrin in iNeutrophil antifungal activity. Collectively, these findings support the use of iNeutrophils as a model to study neutrophil antifungal immunity.

microbiology↗

State and trait serotonin variations interact to shape the intrinsic connectivity and gradient architecture of the brain: a combined TPH2 genetics and tryptophan depletion study

BackgroundSerotonin (5-HT) critically regulates cognitive and emotional functions, and both stable and transient variations in 5-HT signaling have been associated with emotional dysregulations. However, findings regarding the neurofunctional effects of transient 5-HT variations have been highly inconsistent. Therefore, we examined whether individual variations in a central 5-HT-regulating genetic polymorphism (tryptophan hydroxylase 2, TPH2) represent a vulnerability or resilience factor for the effects of acute tryptophan depletion (ATD) on functional brain architecture. MethodThe current study utilized a pharmacogenetic within-subject randomized placebo-controlled resting-state fMRI design with n=53 healthy male participants in combination with spontaneous intrinsic neural activity, functional connectivity, and connectome gradient analyses to compare the neurofunctional effects of ATD-induced transient reduction in central 5-HT signaling between TPH2 genotypes (a priori genotyping for rs4570625, GG n = 25 vs. TT n = 23). ResultsATD induced significant increases in spontaneous neural activity in hippocampal CA1 irrespective of genotype and enhanced communication of this region with the bilateral amygdala and the vmPFC specifically in GG carriers. ATD sharpened the intrinsic connectome gradient architecture in several large-scale networks, including the salience, frontoparietal, and default mode network. ConclusionsOur results identify a potential genetic marker for an increased vulnerability to the neural effects of transient variations in 5-HT signaling on the functional architecture of an anxiety- and stress-related brain circuit. Connectome gradient results underscore the regulatory role of 5-HT on the intricate organization of large-scale networks involved in emotional reactivity and regulation.

neuroscience↗

Distinct roles of the two BRCA2 DNA binding domains in DNA damage repair and replication fork preservation

Homologous recombination (HR) is a highly conserved tool for the removal of DNA double-strand breaks (DSBs) and the preservation of stalled and damaged DNA replication forks. Successful completion of HR requires the tumor suppressor BRCA2. Germline mutations in BRCA2 lead to familial breast, ovarian, and other cancers, underscoring the importance of this protein for maintaining genome stability. BRCA2 harbors two distinct DNA binding domains, one that possesses three oligonucleotide/oligosaccharide binding (OB) folds (known as the OB-DBD), and with the other residing in the C-terminal recombinase binding domain (termed the CTRB-DBD) encoded by the last gene exon. Here, we employ a combination of genetic, biochemical, and cellular approaches to delineate contributions of these two DNA binding domains toward HR and the maintenance of stressed DNA replication forks. We show that OB-DBD and CTRB-DBD confer ssDNA and dsDNA binding capabilities to BRCA2, respectively, and that BRCA2 variants mutated in either DNA binding domain are impaired in the ability to load the recombinase RAD51 onto ssDNA pre-occupied by RPA. While the CTRB-DBD mutant is modestly affected for HR, it exhibits a strong defect in the protection of stressed replication forks. In contrast, the OB-DBD is indispensable for both BRCA2 functions. Our study thus defines the unique contributions of the two BRCA2 DNA binding domains in genome maintenance.

biochemistry↗

Mother-child dyadic interactions shape children's social brain and theory of mind

Social cognition develops through a complex interplay between neural maturation and environmental factors, yet the neurobehavioral mechanisms underlying this process remain unclear. Using a naturalistic fMRI paradigm, we investigated the effects of age and parental caregiving on social brain development and Theory of Mind (ToM) in 34 mother-child dyads. The functional maturity of social brain networks was positively associated with age, while mother-child neural synchronization during movie viewing was related to dyadic relationship quality. Crucially, parenting and child factors interactively shaped social cognition outcomes, mediated by ToM abilities. Our findings demonstrate the dynamic interplay of neurocognitive development and interpersonal synchrony in early childhood social cognition, and provide novel evidence for neurodevelopmental plasticity and reciprocal determinism. This integrative approach, bridging brain, behavior, and parenting environment, advances our understanding of the complex mechanisms shaping social cognition. The insights gained can inform personalized interventions promoting social competence, emphasizing the critical importance of nurturing parental relationships in facilitating healthy social development.

neuroscience↗

An integrated view of the structure and function of the human 4D nucleome

The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.

genomics↗

MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, enhances tumor-microglia crosstalk, and drives immune checkpoint blockade efficacy.

BackgroundGlioblastoma (GB) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) showing limited efficacy in unselected patients. We previously recently established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GB. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain poorly understood. MethodWe conducted in vivo kinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+ T cell responses and performed survival studies to validate the most relevant genes. Additionally, paired single cell RNA- sequencing (scRNA-seq) with p-ERK staining, spatial transcriptomics on GB samples, and ex-vivo slice culture of a BRAFV600E mutant GB tumor treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype. ResultsCRISPR/Cas9 screens identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to CD8+ T cells, and anti-PD-1 across all kinases. Experimentally-induced ERK phosphorylation in gliomas enhanced survival with ICB treatment, led to durable anti-tumoral immunity upon re-challenge and memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells correlated with increased interferon responses, antigen presentation and T cell infiltration in GB. Moreover, spatial transcriptomics and scRNA-seq analysis revealed the modulation of interferon responses by the MAPK/ERK pathway in BRAFV600E human GB cells with ERK1/2 knockout and in slice cultures of human BRAFV600E GB tissue. Notably, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia in slice cultures from BRAFV600E mutant GB. ConclusionOur data indicate that the MAPK/ERK pathway is a critical regulator of GB cell susceptibility to anti-tumoral immunity, modulating interferon responses, and antigen-presentation in glioma cells, as well as tumor cell interaction with microglia. These findings not only elucidate the mechanistic underpinnings of immunotherapy resistance in GB but also highlight the MAPK/ERK pathway as a promising target for enhancing immunotherapeutic efficacy in this challenging malignancy.

cancer biology↗

Optimal transport reveals dynamic gene regulatory networks via gene velocity estimation

Inferring gene regulatory networks from gene expression data is an important and challenging problem in the biology community. We propose OTVelo, a methodology that takes time-stamped single-cell gene expression data as input and predicts gene regulation across two time points. It is known that the rate of change of gene expression, which we will refer to as gene velocity, provides crucial information that enhances such inference; however, this information is not always available due to the limitations in sequencing depth. Our algorithm overcomes this limitation by estimating gene velocities using optimal transport. We then infer gene regulation using time-lagged correlation and Granger causality via regularized linear regression. Instead of providing an aggregated network across all time points, our method uncovers the underlying dynamical mechanism across time points. We validate our algorithm on 13 simulated datasets with both synthetic and curated networks and demonstrate its efficacy on 4 experimental data sets. Author summaryUnderstanding how genes interact to regulate cellular functions is crucial for advancing our knowledge of biology and disease. We present OTVelo, a method that uses single-cell gene expression data collected at different time points to infer gene regulatory networks. OTVelo offers a dynamic view of how gene interactions change over time, providing deeper insights into cellular processes. Unlike traditional methods, OTVelo captures temporal information through ancestor-descendant transitions without assuming a specific underlying regulatory model. We validate our approach using both simulated and real-world data, demonstrating its effectiveness in revealing complex gene regulation patterns. This method could lead to new discoveries in understanding biological systems and developing disease treatments.

bioinformatics↗

Metapipeline-DNA: A Comprehensive Germline & Somatic Genomics Nextflow Pipeline

SummaryThe price, quality and throughout of DNA sequencing continue to improve. Algorithmic innovations have allowed inference of a growing range of features from DNA sequencing data, quantifying nuclear, mitochondrial and evolutionary aspects of both germline and somatic genomes. To automate analyses of the full range of genomic characteristics, we created an extensible Nextflow meta-pipeline called metapipeline-DNA. Metapipeline-DNA analyzes targeted and whole-genome sequencing data from raw reads through pre-processing, feature detection by multiple algorithms, quality-control and data- visualization. Each step can be run independently and is supported robust software engineering including automated failure-recovery, robust testing and consistent verifications of inputs, outputs and parameters. Metapipeline-DNA is cloud-compatible and highly configurable, with options to subset and optimize each analysis. Metapipeline-DNA facilitates high-scale, comprehensive analysis of DNA sequencing data. AvailabilityMetapipeline-DNA is an open-source Nextflow pipeline under the GPLv2 license and is available at https://github.com/uclahs-cds/metapipeline-DNA.

bioinformatics↗

Endogenous retroviruses activate MARCO-mediated inflammatory response to block retroviral infection

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections and can profoundly affect the host antiviral innate immune response, although the mechanisms by which these changes occur are largely unknown. Here we report that chicken-specific ERVs exert genetic resistance to exogenous retrovirus infection. Mechanistically, chicken-specific ERVs activated the scavenger receptor MARCO (macrophage receptor with collagenous structure)-mediated TLR3-IL-1{beta} inflammatory response in macrophages. Under the presence of MARCO, macrophages response to viral infection through inducing TLR3-IL-1{beta} inflammatory response. Conversely, lack of MARCO increased the viral replication levels and attenuated the antiviral inflammatory response. MARCO-mediated ligand delivery enhances TLR3-IL-1{beta} antiviral response, and IL-1{beta} expression is responsible for viral inhibition. Restoring MARCO or IL-1{beta} expression overcomes viral infection in macrophages. Our study provides new insights into the molecular mechanisms underlying the host defense against exogenous retroviruses infection and may have important implications for the development of novel therapeutic strategies against retroviruses infection.

immunology↗