Biology subjects

Collier, J.

Publications and source records attributed to Collier, J..

At least 19 recordsLinked to original sources

bioRxiv2026

DNA catenation is essential for Sister Chromatid Cohesion

From S phase until anaphase, sister chromatids remain physically linked to ensure accurate chromosome segregation. This linkage, called sister chromatid cohesion, must withstand the pulling forces generated by the mitotic spindle and is thought to require entrapment of sister DNAs inside the ring-shaped cohesin complex. DNA catenations that arise naturally during replication could also tether sister chromatids, but whether they contribute to cohesion has remained unresolved. Here, using budding yeast, we show that cohesin-mediated sister DNA entrapment alone cannot withstand spindle-generated pulling forces and that robust sister chromatid cohesion requires DNA catenation. Selective removal of DNA catenations causes catastrophic cohesion loss, delays chromosome biorientation and increases chromosome mis-segregation, even when cohesin rings remain intact. Importantly, DNA catenation similarly underpins force-resistant cohesion in metazoan chromosomes. Our findings fundamentally redefine the physical basis of sister chromatid cohesion by establishing DNA catenation as an evolutionarily conserved component of the force-resistant linkage between sister chromatids that enables accurate chromosome segregation.

molecular biology↗

bioRxiv2026

Genome replication and cell division control by the methylation-sensitive GcrA regulator in Agrobacterium tumefaciens

Bacteria with complex genomes including secondary chromosomes and/or megaplasmids face unique challenges when controlling their cell cycle: they not only need to coordinate genome replication with other cell cycle events such as cell growth and cell division, but also to synchronize the replication of different replicons. In Alphaproteobacteria, replication and maintenance of large extrachromosomal replicons are usually dependent on RepABC modules, as seen for the plant pathogen Agrobacterium tumefaciens. In this study, we demonstrate that the conserved GcrA protein is an essential methylation-dependent transcriptional regulator playing at least two critical roles during the A. tumefaciens cell cycle. First, GcrA is required for the on-time and synchronized firing of the three RepABC-dependent origins of replication of A. tumefaciens that are needed for chromosomal and megaplasmid replication. Second, GcrA triggers the expression of several essential cell division genes for the timely assembly of a functional divisome. These findings highlight how this conserved global regulator can control and then synchronize a variety of essential cell cycle events in Alphaproteobacteria with complex genomes, notably coordinating the maintenance of several RepABC-dependent replicons with cell division. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=47 SRC="FIGDIR/small/728657v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@c7f0f7org.highwire.dtl.DTLVardef@9cf8f1org.highwire.dtl.DTLVardef@19baa05org.highwire.dtl.DTLVardef@b73437_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2026

Temperature-dependent performance scales with maximum heat tolerance across ectotherms

Projecting species responses to changing temperatures remains a major challenge in ecology. Central to this effort is harnessing our understanding of species thermal physiological traits, which underlie ectotherm fitness. These traits are typically characterized by describing performance across temperatures (thermal performance curve, TPC), and/or tolerance limits, which capture endpoints of biological failure. Despite their importance, we still lack an understanding of the functional relationship between these traits, limiting our ability to integrate them into comprehensive vulnerability assessments. Using a synthesized dataset of >100 ectotherms, we tested how heat tolerance (CTmax) relates to key TPC traits: thermal optima, thermal maxima, and the supra-optimal range of temperatures where performance is positive. Across taxa, TPC traits were positively related to CTmax, demonstrating a link between heat tolerance and temperature-dependent performance at sub-critical temperatures. While acute locomotor performance scaled proportionally with CTmax, metabolic processes and sustained locomotion scaled sub-proportionally, suggesting decoupling of CTmax and performance among high-CTmax species. This suggests that using CTmax as a comparative metric may overestimate thermal safety margins for metabolic processes critical to growth. Our results indicate that while CTmax and TPCs reflect shared underlying constraints--particularly in acute neuro-muscular traits--their relationship is dependent on timescale and the TPC response trait. Our findings connect our understanding of the processes that maintain performance over thermal gradients with those that cause performance to fail, improving our ability to project species persistence in a warming world. SignificanceClimate warming is increasingly reshaping the thermal environments that govern species persistence worldwide. Predicting vulnerability requires integrating multiple aspects of thermal biology, yet relationships among widely used thermal traits remain poorly understood. By synthesizing data from more than 100 ectotherm species, we quantify links between acute heat tolerance and traits describing sustained biological function across temperatures. We show that performance at relatively benign temperatures and performance at thermal extremes are coupled, but this coupling is strongly process and timescale dependent, with close correspondence for short term locomotion but weaker coupling for metabolic processes. Our results link the processes that maintain performance across temperatures with those that cause failure, fundamentally advancing our projections of species performance in a warming world.

ecology↗

bioRxiv2026

Harnessing Inflammatory Monocytes to Overcome Resistance to Anti-PD-1 Immunotherapy

BackgroundResistance to immune checkpoint inhibitors represents a major therapeutic challenge, as less than 50% of patients with melanoma achieve long-term response to immune checkpoint inhibitor therapy. One mechanism of acquired resistance involves somatic mutations, such as loss of beta-2 microglobulin (B2m), that enable tumor cells to evade T cell-mediated killing. MethodsThis study used single-cell RNA-seq, flow cytometry, and ex vivo functional assays to characterize tumor-infiltrating immune cells in antigen presentation-deficient tumors. Tumor-bearing mice were treated with anti-PD-1 or CD40 agonist antibodies and cell depletion or cytokine blocking antibodies to define mechanisms of action. Analysis of published human RNA-seq datasets was performed to dissect the contributions of inflammatory monocytes to patient outcomes. ResultsWe found an increase in immunosuppressive macrophages in B2m-null tumors. We hypothesized that repolarizing myeloid cells may restore control of tumor growth. Treatment with CD40 agonist antibody, which promotes differentiation of monocytes and macrophages towards a proinflammatory phenotype, reduced tumor growth and improved survival in B2m-null melanoma and colorectal cancer models. Unexpectedly, both CD8+ T cells and NK cells, but not CD4+ T cells, were required for the efficacy of CD40 agonist, even though CD8+ T cells cannot directly recognize antigen presentation-deficient tumor cells. Instead, these lymphocytes control tumor growth via secretion of IFN{gamma}, as depletion of IFN{gamma} inhibited the therapeutic effect of CD40 agonist. IFN{gamma} receptor (Ifngr1) expression was required on host cells, not tumor cells, for CD40 agonist-mediated tumor control. Single-cell analysis identified a distinct population of inflammatory monocytes that were enriched for an IFN{gamma} response signature in CD40 agonist-treated tumors, suggesting that these cells may be important for tumor control. Analysis of human bulk and single-cell RNA-seq datasets demonstrated that an inflammatory monocyte signature derived from our data was associated with improved patient outcomes and response to immune checkpoint inhibitors. ConclusionsThese data demonstrate that CD8+ T cells contribute to tumor control even in the absence of direct antigen presentation by tumor cells. More broadly, our work suggests that strategies to activate the effector functions of inflammatory monocytes may limit tumor growth and overcome acquired resistance to immune checkpoint inhibitors.

immunology↗

bioRxiv2025

Inferring cellular communication through mapping cells in space using Tangram 2

Cell-to-cell communication (CCC) shapes development, immunity, and disease, yet current spatial transcriptomics (SRT) platforms rarely achieve both single-cell resolution and high-quality transcriptome-wide coverage to accurately characterize CCC in the tissue microenvironment. Tangram2 bridges this gap by integrating single-cell RNA sequencing (scRNA-seq) with SRT to identify genes whose expression changes as a function of neighboring cell types. By accurately mapping cells in tissue space, Tangram2 disentangles interaction-driven transcriptional shifts from intrinsic identity markers, yielding mechanistic CCC maps. Validation across diverse settings--including Slide-tags, co-cultured experiments, human lymph nodes, and simulations--demonstrates high accuracy. Applied to triple-negative breast cancer (TNBC) and cutaneous squamous cell carcinoma (cSCC), Tangram2 recapitulates known biology and uncovers new hypotheses, including various immunosuppressive mechanisms in TNBC and a macrophage-regulatory T-cell circuit associated with survival in cSCC.

genomics↗

bioRxiv2025

Cytosine methylation by ScmA contributes to the fitness of Caulobacter crescentus cells naturally expressing a Vsr-like protein

While methylated cytosines are known to play important roles in eukaryotes, their significance in bacteria remains poorly understood especially when they are added on genomes by DNA methyltransferases that are not parts of restriction-modification systems. The newly named ScmA protein of Caulobacter crescentus is one of these solitary cytosine methyltransferases. Here, we show that it methylates YGCCGGCR motifs introducing thousands of m5C bases on the C. crescentus genome. We also find that wild-type C. crescentus cells easily outcompete{Delta} scmA cells during competition experiments. Transcriptome comparisons and using single-cell fluorescent reporters reveal that a DNA damage response is turned on in a significant proportion of{Delta} scmA cells. We then show that this particular response is strictly dependent on the presence of a Vsr-like protein named VsrA. Eventhough the vsrA gene is surprisingly neither genetically linked with the scmA gene nor with another cytosine methyltransferase gene, VsrA is predicted to encode an endonuclease preventing m5C-to-T mutations. Fluorescence microscopy experiments then show that GFP-VsrA forms foci relatively frequently in stationary phase cells, which may correspond to active repair sites. We propose that VsrA may accidentally create double strand breaks when detecting mismatched bases on the genome of{Delta} scmA cells, leading to their observed loss of fitness. Thus, the presence of vsr-like genes can potentially stabilize genes encoding cytosine methyltransferases in bacterial genomes, providing a potential explanation for the relatively high prevalence of solitary cytosine methyltransferases in bacteria even if some of these do not appear to play an easily detectable regulatory role.

microbiology↗

bioRxiv2025

The SMC Hinge is a Selective Gate for Obstacle Bypass

DNA loop-extruding SMC complexes play vital roles in genome maintenance and DNA immunity. However, the ability of these ring-shaped DNA motors to navigate large DNA-bound obstacles, such as DNA/RNA polymerases and ribosomes in prokaryotes, has remained unclear. Here, we demonstrate that a bacterial SMC Wadjet complex can efficiently bypass obstacles larger than the SMC coiled coil lumen if they are linked to the extruded DNA by single-stranded DNA (ssDNA). This process is mediated by the selective entrapment of the ssDNA linker within the SMC hinge channel, which acts as an obligate gate--permitting ssDNA passage while excluding double-stranded DNA (dsDNA). By threading the linker through the hinge gate as dsDNA is translocated through the SMC motor, the obstacle can follow a trajectory distinct from its associated dsDNA, remaining outside the SMC ring. This mechanism enables continuous dsDNA entrapment while successfully bypassing obstacles. We show that hinges of diverse SMC complexes including eukaryotic condensin and Smc5/6 also selectively accommodate ssDNA, suggesting that hinge bypass is a conserved feature across SMC proteins. We demonstrate that while the hinge domain is essential for obstacle bypass, it is dispensable for loop extrusion, showing that these functions are independent, provided by separate SMC modules. These findings uncover the long-sought function of the SMC hinge toroid and provide the first mechanistic explanation for how DNA-entrapping SMC complexes can extrude loops on chromosomal DNA densely populated with obstacles. Integrating hinge bypass into the DNA loop extrusion model, we propose that the hinge may also facilitate the passage of RNA and peptide, enabling bypass of transcription-associated ribonucleoprotein complexes and other SMC complexes.

molecular biology↗

bioRxiv2024

Long-Term Effects of Early Adolescent Second-Generation Antipsychotic Exposure on Body Weight, Caloric Intake, and Metabolism-Associated Gene Expression

The use of second-generation antipsychotic (SGA) medications in pediatric patients raises concerns about potential long-term adverse outcomes. The current study evaluated the long-term effects of treatment with risperidone or olanzapine on body weight, caloric intake, serum insulin, blood glucose, and metabolism-associated gene expression in C57Bl/6J female mice. Compared to mice treated with vehicle, female mice treated with risperidone or olanzapine gained weight at higher rates during treatment and maintained higher body weights for months following treatment cessation. During high-fat diet feeding, some groups of treated mice gained weight at higher rates than their respective control groups, but the finding was not consistent across experiments. Finally, female mice previously treated with olanzapine also exhibited increased expression of genes associated with inflammation and lipogenesis. These findings suggest that pediatric use of SGA medications that induce excess weight gain during treatment may exert persistent effects on body weight and gene expression and such outcomes may form an important aspect of assessing risk-to-benefit ratios in prescribing decisions.

pharmacology and toxicology↗

bioRxiv2023

DNA methylation by CcrM contributes to genome maintenance in the Agrobacterium tumefaciens plant pathogen

The cell cycle-regulated DNA methyltransferase CcrM is conserved in most Alphaproteobacteria, but its role in bacteria with complex or multicentric genomes remains unexplored. Here, we compare the methylome, the transcriptome and the phenotypes of wild-type and CcrM-depleted Agrobacterium tumefaciens cells with a dicentric genome with two essential replication origins. We find that DNA methylation has a pleiotropic impact on motility, biofilm formation and viability. Remarkably, CcrM promotes the expression of the repABCCh2 operon, encoding proteins required for replication initiation/partitioning at ori2, and inhibits gcrA, encoding a conserved global cell cycle regulator. Imaging ori1 and ori2 in live cells, we show that replication from ori2 is often delayed in cells with a hypo-methylated genome, while ori2 over-initiates in cells with a hyper-methylated genome. We thus propose that methylation by CcrM stimulates RepABC-dependent chromosomal origins, uncovering a novel and original connection between CcrM-dependent DNA methylation and genome maintenance in an Alphaproteobacterial pathogen.

microbiology↗

bioRxiv2023

Chromosome organization shapes replisome dynamics in Caulobacter crescentus

DNA replication in bacteria takes place on highly compacted chromosomes, where segregation, transcription, and repair must occur simultaneously. Within this dynamic environment, colocalization of sister replisomes has been observed in many bacterial species, driving the hypothesis that a physical linker may tether them together. However, replisome splitting has also been reported in many of the same species, leaving the principles behind replisome organization a long-standing puzzle. Here, by tracking the replisome {beta}-clamp subunit in live Caulobacter crescentus, we find that rapid DNA segregation can give rise to a second focus which resembles a replisome, but does not replicate DNA. Sister replisomes can remain colocalized, or split apart to travel along DNA separately upon disruption of chromosome inter-arm alignment. Furthermore, chromosome arm-specific replication-transcription conflicts differentially modify replication speed on the two arms, facilitate the decoupling of the two replisomes. With these observations, we conclude that the dynamic chromosome organization flexibly shapes the organization of sister replisomes, and we outline principles which can help to reconcile previously conflicting models of replisome architecture.

microbiology↗

bioRxiv2023

Pan-genotypic probe-based enrichment to improve efficiency of Hepatitis B virus sequencing

Hepatitis B Virus (HBV) genome sequencing can be used to provide more complete genetic information at the population and individual level to shed light on the limitations of current interventions, and inform new strategies for elimination. HBV sequencing is challenging due to the partially dsDNA genome, high diversity, low viral loads and presence of large amounts of host genetic material in clinical samples. Here we describe the design and use of a pan-genotypic panel of 74 HBV specific capture-probes and nuclease treatment in improving sequencing efficiency. We processed 20 plasma samples (viral loads 1.98 to 4.07 log10, genotypes A-E) and three positive controls (human total brain RNA and bacteriophage lambda DNA) in triplicate to compare DNAse vs. RNAse vs. no nuclease treatment. We prepared libraries using the Takara Bio SMARTer Stranded Total RNA-Seq Kit v3, split the library in two, enriching half with the custom-designed probe panel and xGen Hybridization and Wash Kit (IDT), the other half was not enriched. Both libraries were sequenced on the NovaSeq6000 platform with 2x150nt paired-end reads. Capture resulted in a 47,970 fold increase in the number of reads mapped to the HBV genome in the "no nuclease" arm (243 HBV reads per million reads sequenced in the capture pool vs. 5x10-3 reads per million in the no-capture pool). Out of 20 samples, only 1 without capture generated HBV reads (viral load 3.89 log10 IU/ml) vs. 19 samples with capture. HBV sequence yield was increased in the capture arm and resulted in 2.30 log10 (95% confidence interval 1.99 - 2.48 log10) increase in HBV reads (per million reads sequenced) per log10 increase in viral load. The proportion of HBV reads increased a median of 12 fold with RNAse treatment. We developed a targeted pan-genotypic sequencing method using a custom panel of biotinylated oligos that increases the sequencing efficacy of HBV. This method will allow us to gain a better insight into HBV diversity.

genomics↗

bioRxiv2022

Acinetobase: the comprehensive database and repository of Acinetobacter strains.

BackgroundAcinetobacter baumannii is one of the most problematic nosocomial pathogens that can efficiently thrive within hospital settings, mainly due to resistances towards antibiotics, desiccation, disinfectants, human serum and oxidative stress. Recently, increased resistance against last resort antibiotics earns this bacterium the highest priority concern classified by the CDC and the WHO. An obvious hallmark of this bacterium is the high heterogeneity observed amongst A. baumannii isolates, with a limited core genome. This feature complexifies the study of A. baumannii bacteria as an entity, subsequently reflected in a diversity of phenotypes of not only antimicrobial and environmental resistance but also virulence. Main bodyHigh degree of genome plasticity, along with the use of a limited subset of established reference strains, can lead to strain-specific observations, decreasing the global understanding of this pathogenic agent. Phenotypic variability of A. baumannii strains is easily observable such as with the macrocolony morphologies, in vitro and in vivo virulence, natural competence level, production of different capsular polysaccharide structures and cellular densities. Some strains encode an extensive amount of virulence factors while other, including the reference strains, lack several key ones. The lack/excess of genes or specific physiological processes might interfere with in vivo and in vitro experiments, thus providing limited impact on the global understanding of Acinetobacter bacteria as a whole. ConclusionAs an answer to the high heterogeneity amongst A. baumannii strains, we propose a first comprehensive database that includes the bacterial strains and the associated phenotypic and genetic data. This new repository, freely accessible to the entire scientific community, allow selecting the best bacterial isolate(s) related to any biological question, using an efficient and fast exchange platform.

bioinformatics↗

bioRxiv2020

Spatial coupling between DNA replication and mismatch repair in Caulobacter crescentus

The DNA mismatch repair (MMR) process detects and corrects replication errors in organisms ranging from bacteria to humans. In most bacteria, it is initiated by MutS detecting mismatches and MutL nicking the mismatch-containing DNA strand. Here, we show that MMR reduces the appearance of rifampicin resistances more than a 100-fold in the Caulobacter crescentus Alphaproteobacterium. Using fluorescently-tagged and functional MutS and MutL proteins, live cell microscopy experiments showed that MutS is usually associated with the replisome during the whole S-phase of the C. crescentus cell cycle, while MutL displays an apparently more dynamic association with the replisome. Thus, MMR components appear to use a 1D-scanning mode to search for rare mismatches, although the spatial association between MutS and the replisome is dispensible under standard growth conditions. Conversely, the spatial association of MutL with the replisome appears as critical for MMR in C. crescentus, suggesting a model where the {beta}-sliding clamp licences the endonuclease activity of MutL right behind the replication fork where mismatches are generated. The spatial association between MMR and replisome components may also play a role in speeding up MMR and/or in recognizing which strand needs to be repaired in a variety of Alphaproteobacteria.

microbiology↗

bioRxiv2020

AutoSpill: a method for calculating spillover coefficients in high-parameter flow cytometry

Compensating in classical flow cytometry or unmixing in spectral systems is an unavoidable challenge in the data analysis of fluorescence-based flow cytometry. In both cases, spillover coefficients are estimated for each fluorophore using single-color controls. This approach has remained essentially unchanged since its inception, and is increasingly limited in its ability to deal with high-parameter flow cytometry. Here, we present AutoSpill, a novel approach for calculating spillover coefficients or spectral signatures of fluorophores. The approach combines automated gating of cells, calculation of an initial spillover matrix based on robust linear regression, and iterative refinement to reduce error. Moreover, autofluorescence can be compensated out, by processing it as an endogenous dye in an unstained control. AutoSpill uses single-color controls and is compatible with common flow cytometry software, but it differs in two key aspects from current methods: (1) it is much less demanding in the preparation of controls, as it does not require the presence of well-defined positive and negative populations, and (2) it does not require manual tuning of the spillover matrix, as the algorithm iteratively computes the tuning, producing an optimal compensation matrix. Another algorithm, AutoSpread, complements this approach, providing a robust estimate of the Spillover Spreading Matrix (SSM), while avoiding the need for well-defined positive and negative populations. Together, AutoSpill and AutoSpread provide a superior solution to the problem of fluorophore spillover, allowing simpler and more robust workflows in high-parameter flow cytometry.

immunology↗

bioRxiv2019

HdaB: a novel and conserved DnaA-related protein that targets the RIDA process to stimulate replication initiation

Exquisite control of the DnaA initiator is critical to ensure that bacteria initiate chromosome replication in a cell cycle-coordinated manner. In many bacteria, the DnaA-related and replisome-associated Hda/HdaA protein interacts with DnaA to trigger the regulatory inactivation of DnaA (RIDA) and prevent over-initiation events. In the C. crescentus Alphaproteobacterium, the RIDA process also targets DnaA for its rapid proteolysis by Lon. The impact of the RIDA process on adaptation of bacteria to changing environments remains unexplored. Here, we identify a novel and conserved DnaA-related protein, named HdaB, and show that homologs from three different Alphaproteobacteria can inhibit the RIDA process, leading to over-initiation and cell death when expressed in actively growing C. crescentus cells. We further show that HdaB interacts with HdaA in vivo, most likely titrating HdaA away from DnaA. Strikingly, we find that HdaB accumulates mainly during stationary phase and that it shortens the lag phase upon exit from stationary phase. Altogether, these findings suggest that expression of hdaB during stationary phase prepares cells to restart the replication of their chromosome as soon as conditions improve, a situation often met by free-living or facultative intracellular Alphaproteobacteria.

microbiology↗

bioRxiv2019

The conserved transcriptional regulator CdnL is required for metabolic homeostasis and morphogenesis in Caulobacter

Bacterial growth and division require regulated synthesis of the macromolecules used to expand and replicate components of the cell. Transcription of housekeeping genes required for metabolic homeostasis and cell proliferation is guided by the sigma factor {sigma}70. The conserved CarD-like transcriptional regulator, CdnL, associates with promoter regions where {sigma}70 localizes and stabilizes the open promoter complex. However, the contributions of CdnL to metabolic homeostasis and bacterial physiology are not well understood. Here, we show that Caulobacter crescentus cells lacking CdnL have severe morphological and growth defects. Specifically,{Delta} cdnL cells grow slowly in both rich and defined media, and are wider, more curved, and have shorter stalks than WT cells. These defects arise from transcriptional downregulation of most major classes of biosynthetic genes. Notably, we find that{Delta} cdnL cells are severely limited in glutamate synthesis, rendering them auxotrophic for that amino acid. Moreover,{Delta} cdnL cells produce low amounts of the cell wall precursor lipid II, and{Delta} cdnL is synthetic lethal with other genetic perturbations that limit lipid II production.{Delta} cdnL cells also have aberrant localization of MreB and CtpS, cytoskeletal proteins required for maintaining proper cell width and curvature. Interestingly, the localization of CtpS is dependent on availability of CTP, which is predicted to be low in{Delta} cdnL cells. Our findings implicate CdnL as a global regulator of genes required for metabolic homeostasis that impacts morphogenesis through availability of lipid II and through metabolite-mediated changes in localization of cytoskeletal regulators of cell shape.

microbiology↗

bioRxiv2019

Scc2 counteracts a Wapl-independent mechanism that releases cohesin from chromosomes during G1 but is unnecessary during S phase for establishing cohesion

Cohesins association with chromosomes is determined by loading dependent on the Scc2/4 complex and release due to Wapl. We show here that Scc2/4 is not merely a loading complex and that it actively maintains cohesin on chromosomes during G1. It does so by blocking a Wapl-independent release reaction that requires opening the cohesin ring at its Smc3/Scc1 interface as well as the D loop of Smc1s ATPase. The Wapl-independent release mechanism is switched off as cells activate Cdk1 and enter G2/M and cannot be turned back on without cohesins dissociation from chromosomes. The latter phenomenon enabled us to show that cohesin that has already captured DNA in a Scc2-dependent manner before replication no longer requires Scc2 to capture sister DNAs during S phase.

molecular biology↗

bioRxiv2018

Data from an electronic health informatics pipeline to describe clearance dynamics of Hepatitis B surface antigen (HBsAg) and e-Antigen (HBeAg) in chronic HBV infection

HBsAg and HBeAg have gained traction as biomarkers of control and clearance during monitoring of chronic hepatitis B virus infection (CHB). An improved understanding of the correlates of clearance of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR-HIC), adopting an unbiased approach to generating a robust longitudinal dataset for adults testing HBsAg-positive from a large UK teaching hospital over a six year period (2011-2016 inclusive). From 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. HBsAg clearance rate was similar in individuals on NA therapy (n=4, median clearance time 150 weeks) vs those not on NA therapy (n=9, median clearance time 157 weeks). Those who cleared HBsAg were significantly older, and less likely to be on NA therapy compared to non-clearers (p=0.003 and p=0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (p=0.025). HBeAg clearance occurred both on NA therapy (n=24, median time 49 weeks) and off NA therapy (n=19, median time 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematised approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and underpin improvements in clinical care provision.\n\nIMPORTANCEAdvances in the diagnosis, monitoring and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical datasets that can help to inform advances in patient care, and provide clues that inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been under-represented in the literature. Tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualised clinical care and may provide important clues into the immune events that underpin disease control.

microbiology↗