Biology subjects

Ning, C.

Publications and source records attributed to Ning, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Genetic regulation of circulating metabolome in cattle

The circulating metabolome is a vital intermediate layer linking genetics to complex phenotypes, yet existing genome-wide studies-even in humans-rarely capture dynamic physiological contexts or cellular regulatory mechanisms. Here, we present the Cattle Metabolome Atlas (https://cattlema.farmgtex.org/), a comprehensive resource of 3,436 plasma metabolites and 4,851 serum metabolites from 4,651 animals with matched sequence-level genotypes across highly dynamic parity and lactation stages. We mapped 728 plasma and 622 serum metabolite quantitative trait loci (mQTL), revealing widespread context-dependent regulatory architectures. Integrating these mQTL with the multi-tissue expression quantitative trait loci (eQTL) and single-cell atlas of 59 tissues demonstrates that 74-79% of mQTL colocalize with eQTL across 29 tissues, prioritizing the liver as the primary systemic hub and resolving metabolic programs at single-cell resolution. Furthermore, we charted 538 causal gene-tissue-metabolite-trait cascades across 11 complex traits in cattle. Finally, cross-species analyses demonstrate partial evolutionary conservation of genetic metabolism between cattle and humans, establishing this atlas as a powerful asset for cattle genetics and genomics, selective breeding, and comparative biology.

genetics↗

bioRxiv2026

Dissecting the TMEM132A-EGFR Dependency to Unlock Translational Therapeutic Opportunities for Pan-Solid Tumor

Solid tumors remain refractory to conventional treatments, yet cell surface proteins, by virtue of their extracellular accessibility and critical roles in tumor signaling, represent an attractive class of targets for precision-targeted therapy. Here, we report that TMEM132A is an essential and previously unrecognized pan-cancer target. TMEM132A interacts directly with EGFR and stabilizes its expression, thereby tethering EGFR at the plasma membrane and sustaining constitutive activation of lipid synthesis. Mechanistically, the TMEM132A-EGFR axis promotes lipogenesis by facilitating SREBP nuclear translocation, which in turn upregulates ACLY and ACSS2 expression to drive acetyl-CoA production and downstream lipid biosynthesis, ultimately disrupting lipid droplet homeostasis. To therapeutically target this axis, we developed a nanobody, LFNanoT132A#3, which effectively blocks the TMEM132A-EGFR interaction, abrogates downstream signaling activation, and potently inhibits proliferation across multiple solid tumor types. Notably, LFNanoT132A also exerts robust antitumor activity against H1975 xenografts, a model resistant to first- and second- generation EGFR inhibitors, underscoring its potential to overcome conventional drug resistance. Our findings establish TMEM132A#3 as a critical node in membrane-tethered oncogenic signaling and metabolic rewiring, and position LFNanoT132A#3 as a promising therapeutic candidate for precision cancer therapy.

cancer biology↗

bioRxiv2026

Host genetic regulation of fermentation-related cecal microbial taxa is associated with loin muscle deposition in meat rabbits

Loin muscle weight is an important indicator of carcass yield in meat rabbit production, but the host genetic and intestinal microbial factors associated with its variation remain poorly understood. Because the cecum is the primary site of hindgut fermentation in rabbits, we integrated whole-genome resequencing, cecal transcriptome profiling, and cecal and rectal 16S rRNA sequencing data from 321 Kangda meat rabbits, with rectal microbiome data used as a downstream comparative reference. Compared with the rectum, the cecum contained a richer microbial community, with more ASVs and genera and significantly higher microbial diversity, whereas predicted metabolic functions were largely conserved between the two segments. Loin muscle weight showed moderate SNP-based heritability (h{superscript 2} = 0.39), and the cecal microbiome explained a smaller but detectable proportion of phenotypic variation (m{superscript 2} = 0.13). Multi-strategy microbial screening identified 19 candidate cecal genera associated with loin muscle weight, with Methanosphaera showing the strongest negative association. Host GWAS prioritized candidate loci near MEX3C and TCF4 on chromosome 10, and integration of cecal cis-eQTL and GWAS summary statistics further prioritized GJB3 as a candidate gene associated with loin muscle weight. Consistent with the cecum-centered model, host genetic relatedness was weakly but significantly correlated with cecal microbial similarity, whereas no such global association was observed for the rectal microbiome. Microbial GWAS and SMR analyses further prioritized a cecal MRAP2-Methanobrevibacter association as the main host-regulated microbial signal, while rectal analyses identified distinct segment-specific signals, including SULF1-Roseburia. These findings suggest that host genetic variation may be linked to loin muscle deposition partly through cecal gene expression and fermentation-related cecal microbial taxa, with the rectal microbiome providing comparative evidence for hindgut segment specificity. This study provides candidate host and microbial targets for future functional validation and microbiome-informed nutritional strategies to improve carcass traits in meat rabbits.

genetics↗

bioRxiv2026

A Deep Learning Framework for Spatiotemporal Modeling of Visual Task fMRI

Characterizing the dynamic coordination of distributed brain regions during cognitive tasks remains challenging, as traditional fMRI analysis focuses on localized activations without revealing the underlying information flow that drives them. Here, we propose STREAM (Spatiotemporal Representation for Effective connectivity Analysis Model), a deep-learning framework that learns neural transition functions in task-fMRI to characterize effective connectivity and whole-brain information flow. Applied to visual category processing in 1074 participants, STREAM accurately reconstructs activation maps while further revealing that traditional activation regions are primarily driven by incoming signals. Moreover, the Default Mode Network acts as a high-level regulatory hub with extensive outgoing influence, challenging its passive characterization. Additionally, category-specific communication emerges from dynamic reconfiguration of signaling patterns among key hubs rather than static pathways. These findings establish a novel computational paradigm that uncovers directional signaling mechanisms driving local dynamics in task-fMRI, revealing how the brain flexibly reconfigures functional architecture for complex cognition.

neuroscience↗

bioRxiv2026

VC-RDAgent: An efficient rare disease diagnosis agent via virtual case construction informed by hybrid statistical-metric and hyperbolic-semantic prioritization

While Large Language Models (LLMs) have shown promise in clinical decision support, current Retrieval-Augmented Generation (RAG) paradigms face a fundamental bottleneck in rare disease diagnosis: the scarcity, privacy restrictions, and extreme heterogeneity of real-world patient records. This reliance on sparse or inaccessible data leads to a severe "retrieval mismatch," where the lack of high-quality reference cases causes diagnostic performance to degrade sharply. To break this deadlock, we propose VC-RDAgent, a privacy-preserving and offline-capable framework that decouples diagnostic reasoning from sensitive real-world records by synthesizing virtual standardized cases. The system is powered by VC-Ranker, a multi-dimensional engine that integrates statistical-metric measures with hyperbolic-semantic embeddings to capture deep hierarchical ontology relationships. This approach allows for the dynamic generation of high-fidelity virtual references directly from authoritative knowledge bases. Extensive benchmarking across four diverse datasets demonstrates that VC-RDAgent effectively functions as a "performance equalizer." It boosts average Top-1 hit rates by 8.7% to 85.9% over zero-case baselines, enabling lightweight open-source models to rival frontier commercial systems. Notably, VC-Ranker alone achieved an aggregate Top-10 hit rate of 0.819, outperforming prior state-of-the-art methods by 6%. By eliminating the dependency on real-time web retrieval and private case sharing, VC-RDAgent provides a scalable, robust, and clinically deployable solution to shorten the diagnostic odyssey, which is made accessible through an intuitive, chat-based web application https://rarellm.service.bio-it.tech/rdagent/.

bioinformatics↗

bioRxiv2025

Multiple Routes to Metacognitive Judgments of Working Memory in the Macaque Prefrontal Cortex

The ability to evaluate ones own memory is known as metamemory. Whether metamemory is inherent to memory strength or requires additional computation in the brain remains largely unknown. We investigated the metacognitive mechanism of working memory (WM) using two-photon calcium imaging in the prefrontal cortex of macaque monkeys, who were trained to memorize spatial sequences of varying difficulties. In some trials, after viewing the sequence, monkeys could opt out of retrieval for a smaller reward, reflecting their confidence in WM (meta-WM). We discovered that PFC neurons encoded WM strength by jointly representing the remembered locations through population coding and their associated uncertainties. This WM strength faithfully predicted the monkeys recall performance and opt-out decisions. In addition to memory strength, other factors-- trial history and arousal--encoded in baseline activity predicted opt-out decisions, serving as cues for meta-WM. We identified a code of meta-WM itself that integrated WM strength and these cues. Importantly, WM strength, cues, and meta-WM were represented in different subspaces within the same PFC population. The dynamics and geometry of PFC activity implement metacognitive computations, integrating WM strength with cues into a meta-WM signal that guides behavior.

neuroscience↗

bioRxiv2024

Whole-genome resequencing revealed the Origin and Domestication of Chinese Domestic Rabbits

The evolutionary and genetic origins of Chinese indigenous rabbits (Oryctolagus cuniculus) remain largely unclear, despite being among the most recently domesticated animals. We sequenced the whole genomes of 142 individual rabbits and collected 25 resequencing accessions from the NCBI, representing six Chinese indigenous breeds, three other domesticated breeds (serving as a bridge between European wild-type and Chinese domestic populations), and two wild rabbit populations from the Iberian Peninsula and Southern France. Population and demographic analyses suggest that Chinese domestic rabbits are most likely descendants of O. c. cuniculus, native to France 800-1500 years ago. These rabbits likely first arrived in the southeast coastal areas of China through trade before spreading to inland regions. Additionally, there may be other origins for Chinese domestic rabbits. We observed considerable variation in the genetic makeup of maternal ancestry between Chinese domestic rabbits and European wild populations, with Chinese rabbits possessing unique mitochondrial haplotypes. Our analysis also highlights selective sweeps on genes affecting brain and neuronal development, which may have been under strong positive selection during domestication; genes related to starch digestion and fat metabolism, suggesting an evolutionary adaptation to digest high-starch diets; and the white coat phenotype in rabbits, resulting from selection at the melanogenesis-associated transcription factor locus. Overall, our data provide comprehensive insights into the origin and domestication of rabbits and lay the foundation for genome-based breeding.

evolutionary biology↗

bioRxiv2023

Diversity and adaptability of RNA viruses in rice planthopper, Laodelphax striatellus

Although a large number of insect-specific viruses (ISVs) have recently been discovered from hematophagous insect, studies on ISV diversity and their association with phytophagous insect hosts were still insufficient. A systematic RNA virome investigation was performed for an important plant virus vector, small brown planthopper (SBPH), Laodelphax striatellus. A total number of 22 RNA viruses (including 17 novel viruses) belonging to various families were successfully identified and characterized. Subsequent analysis indicated that the overall RNA virus transcripts per million (TPM) in SBPH was relatively consistent throughout various different developmental stages of the insects, although the titers of individual viruses differ among different insect tissues, suggesting a delicate balance between ISVs and insect hosts. Moreover, analysis of virus-derived small interfering RNA (siRNA) demonstrated that siRNA mediated antiviral immune response of SBPH was activated in response to the replication of the discovered RNA viruses. Additionally, evaluation for potential cross-species ability of SBPH-ISVs showed that certain SBPH ISVs could successfully infect and replicate in another two rice planthoppers, the brown planthopper and the white-backed planthopper, through microinjection. In conclusion, the RNA virome and their adaptability in SBPH revealed in this study will contribute to a better understanding of the intimate relationship between ISVs and the host insects.

microbiology↗

bioRxiv2023

Prothoracicotropic hormone controls female sexual receptivity through the function of ecdysone in pC1 neurons of Drosophila

Female sexual receptivity is essential for reproduction of a species. Neuropeptides play the main role in regulating female receptivity. However, whether neuropeptides regulate female sexual receptivity during the neurodevelopment is unknown. Here we found the peptide hormone prothoracicotropic hormone (PTTH), which belongs to the insect PG axis, negatively regulated virgin female receptivity through ecdysone during neurodevelopment in Drosophila melanogaster. We identified PTTH neurons as doublesex-positive neurons, they regulated virgin female receptivity before the metamorphosis during the 3rd-instar larval stage. PTTH deletion resulted in the increased EcR-A expression in the whole newly formed prepupae. Furthermore, the ecdysone receptor EcR-A in pC1 neurons positively regulated virgin female receptivity during metamorphosis. The decreased EcR-A in pC1 neurons induced abnormal morphological development of pC1 neurons without changing neural activity. Among all subtypes of pC1 neurons, the function of EcR-A in pC1b neurons was necessary for virgin female copulation rate. These suggested that the changes of synaptic connections between pC1b and other neurons decreased female copulation rate. Moreover, female receptivity significantly decreased when the expression of PTTH receptor Torso was reduced in pC1 neurons. This suggested that PTTH not only regulates female receptivity through ecdysone but also through affecting female receptivity associated neurons directly. The PG axis has similar functional strategy as the HPG axis in mammals to trigger the juvenile-adult transition. Our work suggests a general mechanism underlying which the neurodevelopment during maturation regulates female sexual receptivity.

neuroscience↗

bioRxiv2023

Sucrose taste receptors differ in larval and adult stages of a moth

Almost all herbivorous insects feed on plants and use sucrose as a feeding stimulant, but the molecular basis of their sucrose reception remains unclear. Helicoverpa armigera as a notorious crop pest worldwide mainly feeds on reproductive organs of many plant species in the larval stage, and its adult draws nectar. In this study, we determined that the sucrose sensory neurons located in the contact chemosensilla of larval maxillary galeae were 100-1000 times more sensitive to sucrose than those of adult antennae, tarsi and proboscis. Using the Xenopus expression system, we discovered that Gr10 highly expressed in the larval sensilla was specifically tuned to sucrose, while Gr6 highly expressed in the adult sensilla responded to fucose, sucrose and fructose. Moreover, using CRISPR/Cas9, we revealed that Gr10 was mainly used by larvae to detect lower sucrose, while Gr6 was primarily used by adults to detect higher sucrose and other saccharides, which results in differences in selectivity and sensitivity between larval and adult sugar sensory neurons. Our results demonstrate the sugar receptors in this moth are evolved to adapt towards the larval and adult foods with different types and amounts of sugar, and fill in a gap in sweet taste of animals.

ecology↗

bioRxiv2023

A workcell 1.0 for programmable and controlled operation of multiple fluidic chips in parallel.

We developed a versatile lab-on-chip (LOC) workcell that enables the design and automatic execution of experiments on LOC devices, improving how we establish, optimize, and productionalize LOC processes. Key features include direct docking and cooling of native laboratory tubes, programmable reagent mixing and dilutions, parallel operation of multiple chips, precise flowrate and pressure control, clogging detection and response, programmable microscope control, chip temperature regulation, and scheduled cleaning. All functionality is controlled seamlessly from an easy-to-write protocol file, and based on extensible hardware and software infrastructures to promote community development. To showcase the platforms use and versatility, we demonstrate a series of 5 different automated experiments at varying levels of complexity, executed across both Quake-valve and droplet microfluidic systems. In particular, the workcell was instructed to map the parameter regime that generates viable droplets, to allow a user to select diameters and production frequencies of interest for single bacterial cell encapsulation. Furthermore, three out of three days in a row, the platform successfully performed a complex 15.5h long experiment, integrating in a single automated protocol the full core workflow required by a typical protein-characterization lab: protein expression, purification, dilution generation, and quantitative binding characterization (generating 55296 images in the process). Experiments conducted through the workcell are easier to set up, offer increased control over experiment conditions and parameters, and can be heavily parallelized.

bioengineering↗

bioRxiv2022

Triangulation reduces the polygon of error for the history of Transeurasian

In a recent study we used an interdisciplinary approach combining linguistics, archaeology and genetics to analyse the Transeurasian languages1. Our analysis concluded that the early dispersals of these languages were driven by agriculture. A preprint published on this server presents objections to the Transeurasian hypothesis and its association with farming dispersals2. However, close inspection of that text reveals numerous misinterpretations and inconsistencies. In the interest of furthering scientific debate over Transeurasian language and population history, we address the critiques, revising datasets and fine-tuning approaches. The linguistic critique questions the quantity and quality of our datasets. Here we show that the number of surviving cognate sets for Transeurasian is in line with that for well-established language families. In addition, we find that Tian et al.s failure to reject a core of regularly corresponding cognates in the basic vocabulary creates ground for a consensus about the genealogical relatability of the Transeurasian languages. The archaeological critique attempts a re-analysis of one Bayesian test using re-scored data only for northern China. Over half of the suggested re-scorings contain inconsistencies and it is not explained why the re-analysis retains the original data for sites outside northern China, comprising almost 60% of the total. More importantly, the sweeping claim that there is no evidence supporting the prehistoric migrations analysed in our study is not backed by any discussion of the archaeological record. With respect to genetics, the preprint claims a re-analysis showing that the data do not conclusively support the farming-driven dispersal of Turkic, Mongolian, and Tungusic, nor the two-wave spread of farming to Korea. In fact, the only genetic re-analysis presented is limited to samples from Korea and Japan and does not contradict our original conservative modelling of Neolithic individuals with Hongshan and our Bronze Age ones with Upper Xiajiadian. In sum, in bringing multiple lines of evidence together through triangulation, we gained a more balanced and richer understanding of Transeurasian dispersals than each discipline could provide individually. Our research doubtless leaves room for improvement but we remain confident that triangulation did not fail, but rather brought us a step closer to understanding the history of the Transeurasian languages.

evolutionary biology↗

bioRxiv2022

Talaromyces marneffei suppresses human macrophages inflammatory by producing the truncated protein NCOR2-013 via TUT1-regulated alternative splicing

Talaromyces marneffei (T. marneffei) immune-escaping is an important factor for high mortality of talaromycosis. It is currently known that T. marneffei performs these functions through a variety of strategies, however, the role of alternative splicing (AS) in this process is poorly understood. Here we depicted the AS landscape in the macrophage upon T. marneffei infection via high-throughput RNA sequencing. Moreover, we identified a truncated protein of NCOR2/SMRT, namedly NCOR2-013, was significantly upregulated upon T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1/TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Also, we identified TUT1 as the AS regulator that involved in facilitating T. marneffei immune evasion via regulation of NCOR2-013 production. Collectively, the findings indicate that T. marneffei escapes macrophages killing through the TUT1-mediated the alternative splicing of NCOR2-013, which providing a new insight into the molecular mechanisms of T. marneffei immune evasion, and a potential targets for talaromycosis therapy.

microbiology↗

bioRxiv2022

Defining specific cell states of MPTP-induced Parkinson's disease by single-nucleus RNA sequencing

Parkinsons disease (PD), a neurodegenerative disease with the impairment of movement execution that is related to age, genetic and environmental factors. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on cell-gene of PD has not been fully elucidated. By single-nucleus RNA sequencing, we uncovered the PD-specific cells and revealed remarkable changes in their cellular states, including astrocytosis, endothelial cells absence, as well as a cluster of PD-exclusive medium spiny neuron cells. Furthermore, trajectory analysis of astrocyte and endothelial cells populations predicted candidate target gene sets that might be associated with PD. Notably, the detailed regulatory roles of astrocyte-specific transcription factors Dbx2 and Sox13 in PD were first revealed in our work. Finally, we characterized the cell-cell communications of PD-specific cells and found that the overall communication strength was enhanced in PD compared with matched control, especially the signaling pathways of NRXN and NEGR. Our work provides comprehensive overview on the changes of cellular states of the MPTP-induced mouse brain.

neuroscience↗

bioRxiv2022

Cost-effectively dissecting the genetic architecture of complex wool traits in rabbits by low-coverage sequencing

Wool traits of rabbits are important in fiber production and model organism research on hair growth, while the genetic architecture remains obscure. In this study, we focused on wool characteristics in Angora rabbits, a well-known fiber breed. Balancing genotyping cost and variant detection, we proposed low-coverage whole genome sequencing (LCS) followed by genotype imputation for genotyping. Different genotype imputation strategies, sequencing coverages and sample sizes were compared, and we found by BaseVar + STITCH, genotyping reached high accuracy (>0.97) at a depth of 1.0X and a sample size > 300. Multivariate GWAS followed by conditional GWAS and confidence interval estimation of QTLs were used to reveal the genetic architecture of wool traits. Six QTLs were detected with phenotypic variation contribution ranging from 0.42% to 7.50%. Gene-level mapping implicated FGF10 associated with fiber growth and diameter, which supported previous function research on fibroblast growth factor family in other species and provided genetic information for wool rabbit breeding. We suggest LCS as a cost-effective alternative for assessing common variants. GWAS combined with LCS can excavate QTLs and fine-map genes associated with quantitative traits. This study provides a powerful analysis mentality for investigating complex traits, which lays the foundation for genomic breeding.

genetics↗

bioRxiv2022

An Improved Linear Mixed Model for Multivariate Genome-Wide Association Studies

Current methods of multivariate analysis require complete multivariate phenotypes from each individual and have a computational time complexity of O(n2) per SNP, where n is the sample size. We develop an efficient genomic multivariate analysis tool (GMAT) for genome-wide association studies of multiple correlated traits. The new method can handle incomplete multivariate data with missing records and reduce the time complexity to O(n) per SNP. Simulation studies based on known genotypes and phenotypes of actual populations show that GMAT has increased the statistical power with a proper control of false positivity for association studies compared to the conventional linear mixed model (LMM) that removes individuals with incomplete records. Applications to a balanced donkey data and an unbalanced yeast data show that the computational efficiency of the new method has been increased about tens of times faster than the conventional LMM analysis. The GMAT package can be downloaded at https://github.com/chaoning/GMAT.

bioinformatics↗

bioRxiv2021

Maxent modeling for predicting the potential distribution of global talaromycosis

Talaromycosis, an invasive mycosis caused by Talaromyces marneffei (Tm), has rapidly increased in recent years, becoming an emerging pathogenic fungal disease. However, The driving factors and potential distribution of global talaromycosis is still unclear. Here, we developed maxent ecology model using environmental variables, Rhizomys distribution and HIV/AIDS epidemic to forecast ecological niche of talaromycosis worldwhile, as well as Identify the drivering factors. The constructed model had excellent performance with the area under the curve (AUC) of the receiver operating curve (ROC) of 0.997 in training data and 0.991 in testing data. Our model revealed that Rhizomys distribution, mean temperature of warmest quarter, precipitation of wettest month, HIV/AIDS epidemic and mean temperature of driest quarter were the top 5 important variables affecting talaromycosis distribution. In addition to traditional talaromycosis epidemic areas (South of the Yangtze River in China, Southeast Asian and North and Northeast India), our model also identified other potential epidemic regions, inculding parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Our findings has redefined global talaromycosis, discovered hidden high-risk areas and prorvided insights about driving factors of talaromycosis distribution, which will help inform surveillance strategies and improve the effectiveness of public health interventions against Tm infections. Author SummaryOur study aims to explore the spatial ecology of talaromycosis worldwhile. The diseases burden of Talaromycosis, a neglected zoonotic disease, is continuously rising in recent years because of the sheer size of susceptible population in the setting of increased globalization, rising HIV prevalence, and emerging iatrogenic immunodeficiency conditions. Here, we used historic reported talaromycosis cases from 1964 to 2017, combined with environmental factors, Rhizomys distribution and HIV/AIDS epidemic to build an maxent ecology model to define the ecological niche of talaromycosis, then predicting the potential distribution of the disease. The ecological niche of talaromycosis is characterized by a concentrated distribution, which can be cognitively divided into two regions: traditional talaromycosis epidemic areas (South of the Yangtze River in China, Southeast Asian and North and Northeast India), while other potential epidemic regions were predicted in parts of the North of the Yangtze River, Central America, West Coast of Africa, East Coast of South America, the Korean Peninsula and Japan. Our model also identified 5 driving factors affecting talaromycosis distribution. These findings will help demonstrate the global distribution of talaromycosis, discover hidden high-risk areas, and improve the effectiveness of public health interventions against Tm infections.

ecology↗

bioRxiv2021

Talaromyces marneffei promotes M2 polarization of human macrophages by downregulating SOCS3 expression and activating TLR9 pathway

Little is known about how Talaromyces marneffei, a thermally dimorphic fungus that causes substantial morbidity and mortality in Southeast Asia, evades the human immune system. Polarization of macrophages into fungal-inhibiting M1 and fungal-promoting M2 types has been shown to play an important role in the innate immune response against fungal pathogens. This mechanism has not been defined for T. marneffei. Here, we demonstrated that T. marneffei promotes its survival in human macrophages by inducing them towards M2 polarization. Our investigations of the mechanism revealed that T. marneffei infection led to SOCS3 protein degradation by inducing tyrosine phosphorylation, thereby relieving the inhibitory effect of SOCS3 on p-STAT6, a key factor for M2 polarization. Our SOCS3-overexpression experiments showed that SOCS3 is a positive regulator of M1 polarization and plays an important role in limiting M2 polarization. Furthermore, we found that inhibition of TLR9 pathway partially blocked T. marneffei-induced M2 polarization and significantly enhanced the killing activity of macrophages against T. marneffei. Collectively, these results reveal a novel mechanism by which T. marneffei evades the immune response of human macrophages.

microbiology↗