Biology subjects

Ba, X.

Publications and source records attributed to Ba, X..

6 recordsLinked to original sources

bioRxiv2026

OGG1-Binding to Oxidized Guanine Base in Viral DNA Overcomes Epstein-Barr Virus Latency

Epstein-Barr virus (EBV) establishes lifelong latency in human cells and can periodically reactivate, contributing to several cancers. However, the molecular mechanisms that disrupt EBV latency, particularly those driven by oxidative stress, require further investigation. In this study, we provide evidence that oxidative DNA damage, particularly the formation of 8-oxoguanine and its repair enzyme OGG1, is involved in EBV reactivation. We demonstrated that OGG1 is recruited to EBV regulatory regions under oxidative stress conditions and is associated with the transcriptional activation of immediate-early and early lytic genes. Further experiments showed that pharmacological inhibition of OGG1 DNA binding significantly suppressed EBV lytic gene expression, supporting a functional role for OGG1 in viral reactivation. Mechanistically, our findings suggest that OGG1 may contribute to EBV lytic activation through a noncanonical mechanism independent of its glycosylase activity. These findings provide insight into how EBV may exploit host oxidative DNA damage responses to facilitate latency disruption and suggest that targeting OGG1 may offer a potential strategy to limit EBV reactivation and EBV-associated diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/728896v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@7866a7org.highwire.dtl.DTLVardef@9b5f35org.highwire.dtl.DTLVardef@87a87aorg.highwire.dtl.DTLVardef@461005_HPS_FORMAT_FIGEXP M_FIG C_FIG The model illustrates how oxidative DNA damage promotes Epstein-Barr virus (EBV) lytic reactivation through host base excision repair machineryReactive oxygen species (ROS) may induce oxidative modification of guanine to 8-oxoguanine (8-oxoGua) in latent EBV genomes, potentially contributing to OGG1 recruitment to viral regulatory regions. OGG1 binding facilitates the transcriptional activation of immediate-early and early lytic genes, likely through transcription factor recruitment, thereby contributing to the transition from latency to lytic replication. Pharmacological inhibition of OGG1-DNA interaction suppresses this process, highlighting OGG1 as a potential therapeutic target. 8-oxoGua, 7,8-dihydro-8-oxoguanine; OGG1, 8-oxoguanine DNA glycosylase-1. Significance StatementO_LIidentifies a potential mechanism by which ROS-induced oxidative DNA base damage and OGG1 recruitment within the EBV genome may contribute to viral reactivation from latency. C_LIO_LIsuggests that oxidative DNA repair intermediates may serve as regulatory platforms for viral gene expression. C_LIO_LIprovides pharmacological evidence supporting OGG1 as a potential therapeutic target for suppressing EBV reactivation. C_LI

microbiology↗

bioRxiv2026

Prophage and metabolic determinants of Staphylococcus aureus survival to vancomycin identified via TraDIS screening

Reduced vancomycin susceptibility phenotypes in Staphylococcus aureus contribute to treatment failure, yet the genetic determinants of survival under inhibitory vancomycin exposure remain incompletely defined. We performed transposon directed insertion-site sequencing (TraDIS) on a methicillin resistant S. aureus (MRSA) ST398 mutant library following exposure to vancomycin at its minimum inhibitory concentration, identifying 52 genes whose disruption was associated with loss of population survival at inhibitory drug concentrations. Prophage associated loci were the largest functional group, spanning predicted structural and regulatory genes as well as multiple conserved hypothetical proteins. Targeted testing of defined transposon mutants in a USA300 background confirmed that disruption of selected loci impaired growth under vancomycin exposure. Our results highlight the contribution of diverse physiological processes, including metabolism, stress responses, and a prominent role for prophage-associated functions, rather than discrete resistance pathways. Together, these findings indicate that vancomycin tolerance is shaped by the general physiological state of the bacterial cell, including metabolic capacity and stress adaptation. ImportanceTreatment failure in Staphylococcus aureus infections often occurs in the absence of known antibiotic resistance determinants, suggesting that additional survival mechanisms influence therapeutic outcomes. In this study, we identify genetic determinants required for survival during inhibitory vancomycin exposure, revealing a broad role for metabolic functions, stress adaptation, and prophage-associated loci. The prominence of these diverse processes highlights that survival reflects global physiological adaptation rather than discrete resistance pathways. This insight underscores the need to consider cellular physiology and stress responses when developing strategies to prevent antibiotic tolerance and improve treatment efficacy.

microbiology↗

bioRxiv2022

Extended-spectrum beta-lactamase genes traverse the Escherichia coli populations of ICU patients, staff and environment.

Over a three-month period, we monitored the population of extended-spectrum {beta}-lactam-resistant Escherichia coli (ESBL-EC) associated with the patients, staff and environment of an intensive care unit (ICU) in Guangzhou, China. Thirty-four clinical isolates were obtained from the same hospital 12 months later. A total of 165 isolates were characterised and whole-genome sequenced, with 24 isolates subjected to long-read sequencing. The diverse population included representatives of 59 different sequence types (STs). ICU patient and environmental isolates were largely distinct from staff isolates and clinical isolates. We observed five instances of highly similar isolates (0-13 core-gene SNPs) being obtained from different patients or bed unit environments. ESBL resistance in this collection was largely conferred by blaCTX-M genes, which were found in 96.4% of all isolates. The contexts of blaCTX-M genes were diverse, situated in multiple chromosomal positions and in various plasmids. We identified blaCTX-M-bearing plasmid lineages that were present in multiple STs across the surveillance, staff and clinical collections. Closer examination of ISEcp1-blaCTX-M transposition units shed light on the dynamics of their transmission, with evidence for the acquisition of chromosomal copies of blaCTX-M genes from specific plasmid lineages, and for the movement of blaCTX-M-55 from a ST1193 chromosome to a small mobilisable plasmid. A carbapenem-resistant ST167 strain isolated from a patient that had been treated with meropenem and piperacillin-tazobactam contained seven copies of blaCMY-146, which appears to have been amplified by IS1. Our data revealed limited persistence and movement of ESBL-EC strains in the ICU environment, but we observed circulating plasmid lineages playing an essential and ongoing role in shaping the cephalosporin-resistance landscape in the population examined. Impact statementESBL resistance significantly impacts clinical management of E. coli infections in hospitals globally. It is important to understand the structures of ESBL-EC populations carried by hospital patients and staff, their capacity to persist in hospital environments, and the dynamics of mobile genes that drive the spread of ESBL resistance. In our three-month study, ESBL-EC strains found in the ICU environment were strongly associated with patient carriage, but distinct from strains found in staff. However, plasmid lineages carrying blaCTX-M genes were found across the ICU populations and in a collection of clinical isolates obtained one year later. By examining their content and contexts, we have traced the recent histories of chromosomal and plasmid-borne ISEcp1-blaCTX-M transposition units in the ICU population. This allowed us to implicate specific plasmid lineages in the acquisition of chromosomal blaCTX-M genes, even when the plasmids were no longer present, and to detect recent transposition of blaCTX-M-55 from a chromosome to a mobilisable plasmid. Similar high-resolution approaches to the study of mobile genetic elements will be essential if the transmission routes associated with the spread of ESBL resistance are to be understood and subjected to interventions. Data summarySequencing reads are available under NCBI BioProject accession PRJNA907549. The 91 complete plasmid sequences generated in this study are in a supplementary file called pDETEC_collection.fa.

microbiology↗

bioRxiv2021

Half a century of stable antibiotic resistance in livestock-associated Staphylococcus aureus and its dynamic readaptation to humans

Mobile genetic elements (MGEs) are agents of horizontal gene transfer in bacteria, but can also be vertically inherited by daughter cells. Establishing the dynamics that led to contemporary patterns of MGEs in bacterial genomes is central to predicting the emergence and evolution of novel and resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) clonal-complex (CC) 398 is the dominant MRSA in European livestock and a growing cause of human infections. Previous studies have identified three categories of MGEs whose presence or absence distinguishes livestock-associated CC398 from a closely related and less antibiotic-resistant human-associated population. Here we fully characterise the evolutionary dynamics of these MGEs using a collection of 1,180 CC398 genomes, sampled from livestock and humans, over 27 years. We find that the emergence of livestock-associated CC398 coincided with the acquisition of a Tn916 transposon carrying a tetracycline resistance gene, which has been stably inherited for 57 years. This was followed by the acquisition of a type V SCCmec that carries methicillin, tetracycline and heavy metal resistance genes, which has been maintained for 35 years, with occasional truncations and replacements with type IV SCCmec. In contrast, a class of prophages that carry a human immune evasion gene cluster and that are largely absent from livestock-associated CC398, have been repeatedly gained and lost in both human- and livestock-associated CC398. These contrasting dynamics mean that when livestock-associated MRSA is transmitted to humans, adaptation to the human host outpaces loss of antibiotic resistance. In addition, the stable inheritance of resistance-associated MGEs suggests that the impact of ongoing reductions in antibiotic and zinc oxide use in European farms on livestock-associated MRSA will be slow to be realised.

evolutionary biology↗

bioRxiv2021

HAM-ART: An optimised culture-free Hi-C metagenomics pipeline for tracking antimicrobial resistance genes in complex microbial communities.

Shotgun metagenomics is a powerful tool to identify antimicrobial resistance (AMR) genes in microbiomes but has the limitation that extrachromosomal DNA, such as plasmids, cannot be linked with the host bacterial chromosome. Here we present a laboratory and bioinformatics pipeline HAM-ART (Hi-C Assisted Metagenomics for Antimicrobial Resistance Tracking) optimised for the generation of metagenome-assembled genomes including both chromosomal and extrachromosomal AMR genes. We demonstrate the performance of the pipeline in a study comparing 100 pig faecal microbiomes from low- and high-antimicrobial use pig farms (organic and conventional farms). We found significant differences in the distribution of AMR genes between low- and high-antimicrobial use farms including a plasmid-borne lincosamide resistance gene exclusive to high-antimicrobial use farms in three species of Lactobacilli. Author SummaryAntimicrobial resistance (AMR) is one of the biggest global health threats humanity is facing. Understanding the emergence and spread of AMR between different bacterial species is crucial for the development of effective countermeasures. In this paper we describe a user-friendly, affordable and comprehensive (laboratory and bioinformatics) workflow that is able to identify, associate and track AMR genes in bacteria. We demonstrate the efficiency and reliability of the method by comparing 50 faecal microbiomes from pig farms with high-antibiotic use (conventional farms), and 50 faecal microbiomes from pig farms with low-antibiotic use (organic farms). Our method provides a novel approach to resistance gene tracking, that also leads to the generation of high quality metagenomic assembled genomes that includes genes on mobile genetic elements, such as plasmids, that would not otherwise be included in these assembled genomes.

bioinformatics↗

bioRxiv2021

A survey of Chinese pig farms and human healthcare isolates reveals separate human and animal MRSA populations

There has been increasing concern that the overuse of antibiotics in livestock farming is contributing to the burden of antimicrobial resistance in people. Farmed animals in Europe and North America, particularly pigs, provide a reservoir for livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA, ST398) found in people. This study was designed to investigate the contribution of MRSA from Chinese pig farms to human infection and carriage.A collection of 603 S. aureus were isolated from 55 pig farms and 4 hospitals (MRSA= 285, 198; MSSA= 50, 70) in central China, a high pig farming density area, during 2017-2018. CC9 MRSA accounting for 93% of all farm MRSA isolates, while no was found in hospitals. ST398 isolates were found on three farms (n = 23) and three hospitals (n = 12). None of the ST398 from this study belong to the livestock clade of the LA-MRSA commonly found in Europe and North America. The hospital ST398 MRSA isolates formed a clade that was clearly separate from the farm ST398 MRSA and MSSA isolates, and all possessed human immune evasion cluster genes which were absent from all the pig farm ST398 isolates. Despite the presence of high levels of MRSA found on Chinese pig farms we found no evidence of them spilling over to the human population. Nevertheless, the ST398 MRSA obtained from human samples appear to be part of a widely distributed lineage in China. And the new animal adapted ST398 lineage that emerged in China should also be alarmed. ImportanceWe disclosed the fact that although the high MRSA positive rate in Chinese hospitals and pig farms should be alarmed, they might be two separate issues. The new CC398 clades we identified highlight that the host adaption of the MRSA lineage is kept changing. These results suggest that continued surveillance of MRSA in livestock is necessary. We found that the pig farm MRSA isolates had unique antimicrobial resistance genes while most of the hospital MRSA isolates had human immune evasion cluster genes. These features could be used to distinguish the pig farm associated S. aureus in clinical laboratories. The policies of reducing antimicrobials use in livestock were implemented in China since 2020. Our study described the situation of MRSA populations in pig farms and hospitals in Central China before 2020, which provides a potential opportunity for future studies to evaluate the effects of the policies.

microbiology↗