Biology subjects

Li, G.

Publications and source records attributed to Li, G..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

Coordinated molecular and ecological adaptations underlie a highly successful parasitoid

The success of an organism depends on the molecular and ecological adaptations that promote its beneficial fitness. Parasitoids are valuable biocontrol agents for successfully managing agricultural pests, and they have evolved diversified strategies to adapt to both the physiological condition of hosts and the competition of other parasitoids. Here, we deconstructed the parasitic strategies in a highly successful parasitoid, Trichopria drosophilae, which parasitizes a broad range of Drosophila hosts, including the globally invasive species D. suzukii. We found that T. drosophilae had developed specialized venom proteins that arrest host development to obtain more nutrients via secreting tissue inhibitors of metalloproteinases (TIMPs), as well as a unique type of cell-- teratocytes--that digest host tissues for feeding by releasing trypsin proteins. In addition to the molecular adaptations that optimize nutritional uptake, this pupal parasitoid has evolved ecologically adaptive strategies including the conditional tolerance of intraspecific competition to enhance parasitic success in older hosts and the obligate avoidance of interspecific competition with larval parasitoids. Our study not only demystifies how parasitoids weaponize themselves to colonize formidable hosts but also provided empirical evidence of the intricate coordination between the molecular and ecological adaptations that drive evolutionary success.

ecology↗

bioRxiv2024

Polaris Neurosense: A General-Purpose Non-invasive Neurotechnology Research Platform

This article describes our initial work toward a general-purpose platform for non-invasive neurotechnology research. This platform consists of a multi-modal wireless recording device, an associated software API, and full integration into BCI2000 software. The device is placed on the forehead and features two electroencephalographic (EEG) sensors, an inertial movement sensor (IMU), a photoplethysmogram (PPG) sensor, a microphone, and vibration-based feedback. Herein, we demonstrate different technical characteristics of our platform and its use in the context of sleep monitoring/modulation, simultaneous and synchronized recordings from different hardware, and evoked potentials. With further development and widespread dissemination, our platform could become an important tool for research into new non-invasive neurotechnology protocols in humans.

bioengineering↗

bioRxiv2024

Development of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase

DNA base editors could enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here, by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants, we developed a deaminase-free glycosylase-based thymine base editor (gTBE) with the ability of direct T editing. By several rounds of UNG mutagenesis via rational screening, we demonstrated that gTBE with engineered UNG variants could achieve T editing efficiency by up to 81.5%. Furthermore, the gTBE exhibited high T-to-S (i.e., T-to-C or T-to-G) conversion ratio with up to 0.97 in cultured human cells. Using similar strategy, we developed a deaminase-free cytosine base editor (gCBE) facilitating specifically direct C editing by engineered UNG with mutations different from gTBE. Thus, we provide two novel base editors, gTBE and gCBE, with corresponding engineered UNG variants, broadening the targeting scope of base editors.

molecular biology↗

bioRxiv2023

A highly contiguous hexaploid wheat genome assembly facilitates analysis of 1RS translocation and mining of a new adult plant resistance locus to yellow rust disease

High-quality genome information is essential for efficiently deciphering and improving crop traits. Here we report a highly contiguous hexaploid genome assembly for the key wheat breeding parent Zhou8425B, an elite 1BL/1RS translocation line with durable adult plant resistance (APR) against rust diseases. By using HiFi and Hi-C sequencing reads, a 14.75 Gb genome assembly, with contig N50 and scaffold N50 values reaching 70.94 and 735.11 Mb, respectively, was developed. Comparison with 16 previously sequenced common wheat cultivars revealed unique chromosomal structural features in Zhou8425B. Notably, the 1RS translocation in Zhou8425B was apparently longer and carried more genes encoding AP2/ERF-ERF and B3 transcription factors relative to its counterpart in several genome sequenced 1BL/1RS varieties and rye lines. Aided by Zhou8425B genome assembly, a new APR locus (i.e., YrZH3B) against yellow rust (YR) disease was finely mapped to a 1 - 2 Mb interval on chromosome 3BS. Analysis with 212 Zhou8425B derivative varieties showed that pyramiding of YrZH3B with two other APR loci (YrZH22 and YrZH84) significantly decreased YR severity and enhanced grain yield, with triple combination (YrZH3B/YrZH22/YrZH84) having the highest effects. Our data demonstrate the high value of Zhou8425B assembly in studying wheat genome and agronomically important genes.

genomics↗

bioRxiv2023

Aberrant connective tissue sheath contraction drives premature hair follicle regression by inducing progenitor cell depletion in androgenetic alopecia

Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair, forming a distinctive patterned baldness in the scalp; yet, the mechanisms for hair miniaturization in this disease remain largely unknown. Here by single-cell transcriptome analysis, we describe a concise single-cell atlas, and identify the early changes in cell subpopulations, hair follicle (HF) stem cell fate determination and cell-cell communications in AGA anagen HF units. Thereinto, apoptotic loss of HF progenitor cells is significantly increased, correlated with HF miniaturization in AGA. Mechanistically, enhanced contraction of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1, which triggers ectopic apoptosis of progenitor cells in human anagen HFs. Continuous CTS contraction during AGA causes long-term loss of progenitor cells via inducing persistent ectopic apoptosis through PIEZO1, eventually leading to premature hair regression. Most importantly, we show that targeting CTS contraction by ML-7, a selective myosin light chain kinase (MLCK) inhibitor, can obviously improve the growth of HFs from balding scalps of AGA patients. Our study reveals the cellular hierarchies and identifies CTS with increased muscle contraction activity as a driver of premature hair regression in AGA, highlighting CTS surrounding human HF as the therapeutic target for treating this disorder.

pathology↗

bioRxiv2023

Comprehensive Assessment of Ischemic Stroke in Nonhuman Primates: Neuroimaging, Behavioral, and Serum Proteomic Analysis

Ischemic strokes, prevalence and impactful, underscore the necessity of advanced research models closely resembling human physiology. O integrating n ur study in nonhuman primates (NHPs) offers a comprehensive exploration of ischemic stroke, integrating neuroimaging data, behavioral outcomes, and serum proteomics to elucidate the complex interplay of factors involved in stroke pathophysiology. We observed a consistent pattern in infarct volume, peaking at 1-month post-middle cerebral artery occlusion (MCAO) and stabilizing thereafter. This trend was closely correlated with notable changes in motor function and working memory performance. Using diffusion tensor imaging (DTI), we detected significant alterations in fractional anisotropy (FA) and mean diffusivity (MD) values, indicative of microstructural changes in the brain. These findings were strongly correlated with the observed neurological and cognitive deficits, highlighting the sensitivity of DTI metrics in stroke assessment. Behaviorally, the monkeys exhibited a reliance on their unaffected limb for compensatory movements, a response commonly observed in stroke impairment. This adaptation, alongside the consistent findings in DTI metrics, suggests a substantial impact of stroke on motor function and spatial perception. Proteomic analysis through MS/MS functional enrichment revealed two distinct groups of proteins with significant changes post-MCAO. Notably, MMP9, THBS1, MB, PFN1, and YWHAZ emerged as potential biomarkers and therapeutic targets in ischemic stroke. Our findings underscore the complex nature of stroke and the potential of an integrated approach, combining neuroimaging, behavioral studies, and proteomics, for advancing our understanding and treatment of this condition.

neuroscience↗

bioRxiv2023

Mutation of OsCDS5 confers broad-spectrum disease resistance in rice

Phospholipids are important components of biological membranes, participating in various biological processes, including plant development and responses to biotic and abiotic stresses. A previous study showed that mutation of the rice OsCDS5 (CDP-DAG Synthase) gene alters lipid metabolism, causing enhanced abiotic stress responses, yellowing of leaves at the seedling stage and delayed plant development. Here, we observed that the Oscds5 mutant shows enhanced resistance to rice blast, bacterial blight and bacterial leaf streak. Mutation of OsCDS5 promotes production of reactive oxygen species (ROS) and increases the expression level of multiple defense-related genes. Transcriptomic analyses indicate that genes involved in responses to stress, biotic/abiotic stimuli and metabolic processes are highly upregulated and enriched in mutant Oscds5. Metabolomic analyses show that differential metabolites are enriched in the lipid metabolic and tryptophan metabolic pathways. The decreased level of phosphatidylinositol (PI) and increased level of serotonin likely contribute to enhanced disease resistance of the Oscds5 mutant. Taken together, mutation of OsCDS5 enhances abiotic and biotic stress responses, and OsCDS5 may be a promising target in genetic engineering to enhance the resilience of rice to abiotic and biotic stresses simultaneously.

plant biology↗

bioRxiv2023

The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity

Actinobacteria, the bacterial phylum most renowned for natural product discovery, has been established as a valuable source for drug discovery and biotechnology but is underrepresented within accessible genome and strain collections. Herein, we introduce the Natural Products Discovery Center (NPDC), featuring 122,449 strains assembled over eight decades, the genomes of the first 8490 NPDC strains (7142 Actinobacteria), and the online NPDC Portal making both strains and genomes publicly available. A comparative survey of RefSeq and NPDC Actinobacteria highlights the taxonomic and biosynthetic diversity within the NPDC collection, including three new genera, hundreds of new species, and [~]7000 new gene cluster families. Selected examples demonstrate how the NPDC Portals strain metadata, genomes, and biosynthetic gene clusters can be leveraged using genome mining approaches. Our findings underscore the ongoing significance of Actinobacteria in natural product discovery, and the NPDC serves as an unparalleled resource for both Actinobacteria strains and genomes.

microbiology↗

bioRxiv2023

Application of slow-controlled release fertilizer coordinates the carbon flow in carbon-nitrogen metabolism to effect rice quality

Slow-controlled release fertilizers are experiencing a popularity in rice cultivation due to their effectiveness in yield and quality with low environmental costs. However, the underlying mechanism by which these fertilizers regulate grain quality remains inadequately understood. This study investigated the effects of five fertilizer management practices on rice quality in a two-year field experiment: CK, conventional fertilization, and four applications of slow-controlled release fertilizer (UF, urea formaldehyde; SCU, sulfur-coated urea; PCU, polymer-coated urea; BBF, controlled-release bulk blending fertilizer). In 2020 and 2021, the yields of UF and SCU groups showed significant decreases when compared to conventional fertilization, accompanied by a decline in nutritional quality. Additionally, PCU group exhibited poorer cooking and eating qualities. However, BBF group achieved increases in both yield (10.8 t hm-2 and 11.0 t hm-2) and grain quality reaching the level of CK group. The sufficient nitrogen supply in both the PCU and BBF groups during the grain-filling stage led to a greater capacity for the accumulation of proteins and amino acids in the PCU group compared to starch accumulation. Intriguingly, BBF group showed better carbon-nitrogen metabolism than that of PCU group. The optimal nitrogen supply present in BBF group suitable boosted the synthesis of amino acids involved in the glycolysis/ tricarboxylic acid cycle, thereby effectively coordinating carbon-nitrogen metabolism. The application of the new slow-controlled release fertilizer, BBF, is advantageous in regulating the carbon flow in the carbon-nitrogen metabolism to enhance rice quality.

plant biology↗

bioRxiv2023

Combined Partial-Nitrification and Phosphorus Removal with the co-existence of Nitrite-resistant phosphorous accumulating organisms (PAOs) and nitrifiers in the treatment of high-strength manure digestate

Concurrent biological phosphorus (P) recovery and nitrogen (N) removal in treating high-strength wastewater (such as anaerobic digestate) has been considered incompatible due to presumed conflicts in the conflicting optimum conditions required by phosphorous accumulating organisms (PAO) and nitrifiers. However, this study achieved a stable nitrite accumulation while still maintained PAO activities in one sequencing batch reactor for treating the manure digestate under two aeration schemes (continuous versus intermittent aeration). Nitrite accumulated up to 80.5 {+/-} 21.1 mg-N/L under continuous aeration (6 h) mode. Switching to intermittent aeration (equivalent to 3 h) halved nitrite accumulation but increased total nitrogen removal efficiency from 53.5 {+/-} 12.2% to 84.7 {+/-} 9.4%. Mass balance analysis indicates that nearly all ammonia was removed as N2O. Both Enhanced Biological Phosphorus Removal (EBPR) activity assessment and phenotypic trait detection via single cell Raman spectrum (SCRS) confirmed the existence of yet to be identified PAOs that are resistant to high nitrite inhibition in our system. Visual Minteq calculation indicates that high concentrations of Ca in manure digestate may form precipitates and influence the bioavailability of P forms. Therefore, both biotic and abiotic pathways lead to a total P removal rate around 61.0 {+/-} 6.8%. This study highlights new opportunities to combine short-cut nitrogen removal via partial nitrification, nitrous oxide (N2O) collection, and EBPR in commercial farm-collected digested manure wastewater. Higher N and P removal efficiency could potentially be achieved by tuning aeration schemes in combination with down-stream anammox process. SynopsisConcurrent partial nitrification, N2O accumulation, and EBPR activity were found, leading to the exploration of novel nitrite-resistant PAOs, simultaneously N/P recovery, and waste-energy conversion in treating high strength wastewater.

microbiology↗

bioRxiv2023

DNA Methylation (DM) data format and DMtools for efficient DNA methylation data storage and analysis

DNA methylation is a critical epigenetic mechanism that plays a pivotal role in various biological processes. Currently, larger datasets from whole-genome bisulfite sequencing for DNA methylation pose challenges throughout the computational analysis pipeline, including storage and memory constraints. Unfortunately, storage formats and analysis tools have not kept pace with these increased resource demands. In this study, we present a new and efficient design for storing DNA methylation (DM) data after mapping in compressed binary indexed DM format. Our format significantly reduces storage space by 80%-95% compared to commonly used file formats for DNA methylation data after mapping. To enhance the processing of DNA methylation data in DM format, we have developed DMtools, a comprehensive toolkit that offers utilities such as rapid and random access, computation of DNA methylation profiles across genes, and analysis of differential DNA methylation. The analysis speed is improved by over 100 times compared to existing methods. Furthermore, we have created pyDMtools, a Python package that efficiently processes DM format files for Python users. The integration of the DM format and its associated tools represents significant progress in handling and exploring DNA methylation data, offering the potential to significantly reduce storage needs and improve downstream analysis capabilities.

bioinformatics↗

bioRxiv2023

RAG-17: A Novel siRNA Conjugate Demonstrating Efficacy in Late-Stage Treatment of SOD1G93A ALS mice

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkable in vitro stability and target specificity with minimal immunostimulation. In vivo studies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1G93A ALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.

pharmacology and toxicology↗

bioRxiv2023

Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation Via Hexosamine Biosynthetic Pathway

Age is a prominent risk factor for cardiometabolic disease, and often leads to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction resulting from physiological aging per se remain elusive. Understanding these mechanisms requires biological models with optimal translation to humans. Previous research demonstrated that baboons undergo age-related reduction in ejection fraction and increased heart sphericity, mirroring changes observed in humans. The goal of this study was to identify early cardiac molecular alterations that precede functional adaptations, shedding light on the regulation of age-associated changes. We performed unbiased transcriptomics of left ventricle (LV) samples from female baboons aged 7.5-22.1 years (human equivalent [~]30-88 years). Weighted-gene correlation network and pathway enrichment analyses were performed to identify potential age-associated mechanisms in LV, with histological validation. Myocardial modules of transcripts negatively associated with age were primarily enriched for cardiac metabolism, including oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid {beta}-oxidation. Transcripts positively correlated with age suggest upregulation of glucose uptake, pentose phosphate pathway, and hexosamine biosynthetic pathway (HBP), indicating a metabolic shift towards glucose-dependent anabolic pathways. Upregulation of HBP commonly results in increased glycosaminoglycan precursor synthesis. Transcripts involved in glycosaminoglycan synthesis, modification, and intermediate metabolism were also upregulated in older animals, while glycosaminoglycan degradation transcripts were downregulated with age. These alterations would promote glycosaminoglycan accumulation, which was verified histologically. Upregulation of extracellular matrix (ECM)-induced signaling pathways temporally coincided with glycosaminoglycan accumulation. We found a subsequent upregulation of cardiac hypertrophy-related pathways and an increase in cardiomyocyte width. Overall, our findings revealed a transcriptional shift in metabolism from catabolic to anabolic pathways that leads to ECM glycosaminoglycan accumulation through HBP prior to upregulation of transcripts of cardiac hypertrophy-related pathways. This study illuminates cellular mechanisms that precede development of cardiac hypertrophy, providing novel potential targets to remediate age-related cardiac diseases.

molecular biology↗

bioRxiv2023

Simultaneously-recorded cholinergic axons and cortical acetylcholine are highly correlated with pupil size and locomotion under spontaneous conditions

Even under spontaneous conditions and in the absence of changing environmental demands, awake animals alternate between increased or decreased periods of alertness. These changes in brain state can occur rapidly, on a timescale of seconds, and neuromodulators such as acetylcholine (ACh) are thought to play an important role in driving these spontaneous state transitions. Here, we perform the first simultaneous imaging of ACh sensors and GCaMP-expressing axons in vivo, to examine the spatiotemporal properties of cortical ACh activity and release during spontaneous changes in behavioral state. We observed a high correlation between simultaneously recorded basal forebrain axon activity and neuromodulator sensor fluorescence around periods of locomotion and pupil dilation. Consistent with volume transmission of ACh, increases in axon activity were accompanied by increases in local ACh levels that fell off with the distance from the nearest axon. GRAB-ACh fluorescence could be accurately predicted from axonal activity alone, providing the first validation that neuromodulator axon activity is a reliable proxy for nearby neuromodulator levels. Deconvolution of fluorescence traces allowed us to account for the kinetics of the GRAB-ACh sensor and emphasized the rapid clearance of ACh for smaller transients outside of running periods. Finally, we trained a predictive model of ACh fluctuations from the combination of pupil size and running speed; this model performed better than using either variable alone, and generalized well to unseen data. Overall, these results contribute to a growing understanding of the precise timing and spatial characteristics of cortical ACh during fast brain state transitions.

neuroscience↗

bioRxiv2023

Structure of scavenger receptor SCARF1 and its interaction with lipoproteins

SCARF1 (Scavenger receptor class F member 1, SREC-1 or SR-F1) is a type I transmembrane protein that recognizes multiple endogenous and exogenous ligands such as modified low-density lipoproteins (LDL) and is important for maintaining homeostasis and immunity. But the structural information and the mechanisms of ligand recognition of SCARF1 are largely unavailable. Here we solve the crystal structures of the N-terminal fragments of human SCARF1, which show that SCARF1 forms homodimers and its epidermal growth factor (EGF)-like domains adopt a long-curved conformation. Then we examine the interactions of SCARF1 with lipoproteins and are able to identify a region on SCARF1 for recognizing modified LDLs. The mutagenesis data show that the positively charged residues in the region are crucial for the interaction of SCARF1 with modified LDLs, which is confirmed by making chimeric molecules of SCARF1 and SCARF2. In addition, teichoic acids, a cell wall polymer expressed on the surface of gram-positive bacteria, are able to inhibit the interactions of modified LDLs with SCARF1, suggesting the ligand binding sites of SCARF1 might be shared for some of its scavenging targets. Overall, these results provide mechanistic insights into SCARF1 and its interactions with the ligands, which are important for understanding its physiological roles in homeostasis and the related diseases.

biophysics↗

bioRxiv2023

Is M1-L121E a good mimic on microbial rhodopsin? A viewpoint from excited-state dynamics

Microbial rhodopsin, an important photoreceptor protein, has been widely used in several fields, such as optogenetics, biotechnology, and biodevices etc. However, current microbial rhodopsins are all transmembrane proteins, which both complicates the investigation on the photoreaction mechanism and limits their further applications. Therefore, a suitable mimic for microbial rhodopsin can not only provide a better model for understanding the mechanism, but also can extend the applications. The human protein CRABPII turns out to be a good template for design mimics on rhodopsin, due to the convenience in synthesis and the stability after mutations. Recently, Geiger et al. designed a new CRABPII-based mimic M1-L121E on microbial rhodopsin with the correct 13-cis (13C) isomerization after irritation. However, it still remains a question how similar it is compared with the natural microbial rhodopsin, in particular in the aspect of the photoreaction dynamics. In this article, we investigated the excited-state dynamics of this mimic by measuring its transient absorption spectra. Our results reveal that there are two components in the solution of mimic M1-L121E at PH=8, known as protonated Schiff base (PSB) and unprotonated Schiff base (USB) states. In both states, the photoreaction process from 13-cis (13C) to all-trans (AT) is faster than that from the inverse direction. In addition, the photoreaction process in PSB state is faster than that in the USB state. In the end, we compared the isomerization time of the PSB state with the properties of the microbial rhodopsin, and confirmed that the mimic M1-L121E indeed captures the main feature of the rhodopsin and is a good model of microbial rhodopsin in the photoreaction dynamics. However, our results also reveal significant differences in the excited-state dynamics of the mimic relative to the natural microbial rhodopsin, including the slower PSB isomerization rates in both 13C-AT and AT-13C directions, as well as the unusual USB photoreaction dynamics at PH=8. Such unique properties have not been observed in the natural rhodopsin, which could further deepen the understanding in photoreaction mechanism of the photosensitive proteins.

biophysics↗

bioRxiv2023

Pseudotime analysis for time-series single-cell sequencing and imaging data

Many single-cell RNA-sequencing studies have collected time-series data to investigate transcriptional changes concerning various notions of biological time, such as cell differentiation, embryonic development, and response to stimulus. Accordingly, several unsupervised and supervised computational methods have been developed to construct single-cell pseudotime embeddings for extracting the temporal order of transcriptional cell states from these time-series scRNA-seq datasets. However, existing methods, such as psupertime, suffer from low predictive accuracy, and this problem becomes even worse when we try to generalize to other data types such as scATAC-seq or microscopy images. To address this problem, we propose Sceptic, a support vector machine model for supervised pseudotime analysis. Whereas psupertime employs a single joint regression model, Sceptic simultaneously trains multiple classifiers with separate score functions for each time point and also allows for non-linear kernel functions. Sceptic first generates a probability vector for each cell and then aims to predict chronological age via conditional expectation. We demonstrate that Sceptic achieves significantly improved prediction power (accuracy improved by 1.4 - 38.9%) for six publicly available scRNA-seq data sets over state-of-the-art methods, and that Sceptic also works well for single-nucleus image data. Moreover, we observe that the pseudotimes assigned by Sceptic show stronger correlations with nuclear morphology than the observed times, suggesting that these pseudotimes accurately capture the heterogeneity of nuclei derived from a single time point and thus provide more informative time labels than the observed times. Finally, we show that Sceptic accurately captures sex-specific differentiation timing from both scATAC-seq and scRNA-seq data.

genomics↗

bioRxiv2023

Intrinsic p53 Activation Restricts Gammaherpesvirus-Driven Germinal Center B Cell Expansion during Latency Establishment

Gammaherpesviruses (GHV) are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center (GC) B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of GHV pathogenesis, we demonstrate in vivo that tumor suppressor p53 is activated specifically in B cells that are latently infected by MHV68. In the absence of p53, the early expansion of MHV68 latency was greatly increased, especially in GC B cells, a cell-type whose proliferation was conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of GC B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that EBV-encoded latent membrane protein 1 (LMP1) similarly triggers a p53 response in primary B cells. Our data highlight a model in which GHV latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53. IMPORTANCEGammaherpesviruses cause lifelong infections of their hosts, commonly referred to as latency, that can lead to cancer. Latency establishment benefits from the functions of viral proteins that augment and amplify B cell activation, proliferation, and differentiation signals. In uninfected cells, off-schedule cellular differentiation would typically trigger anti-proliferative responses by effector proteins known as tumor suppressors. However, tumor suppressor responses to gammaherpesvirus manipulation of cellular processes remain understudied, especially those that occur during latency establishment in a living organism. Here we identify p53, a tumor suppressor commonly mutated in cancer, as a host factor that limits virus-driven B cell proliferation and differentiation, and thus, viral colonization of a host. We demonstrate that p53 activation occurs in response to viral latency proteins that induce B cell activation. This work informs a gap in our understanding of intrinsic cellular defense mechanisms that restrict lifelong GHV infection.

microbiology↗