Biology subjects

Hibberd, M. L.

Publications and source records attributed to Hibberd, M. L..

6 recordsLinked to original sources

bioRxiv2026

Menaquinone depletion resensitises bedaquiline-resistant tuberculosis

Tuberculosis remains a leading cause of global mortality, and rising bedaquiline resistance threatens the effectiveness of current drug-resistant treatment regimens. Bedaquiline resistance typically arises through mutations in Rv0678 that upregulate drug efflux and confer cross-resistance to multiple drug classes. Here, we identify and optimise a chemical series targeting MenG, a central enzyme in the menaquinone biosynthesis pathway, yielding potent bactericidal inhibitors with in vivo efficacy. Strikingly, MenG inhibition restored bedaquiline susceptibility in efflux-mediated resistant strains, an effect confirmed in vivo where combination therapy achieved a 99.8% reduction in bacterial burden compared with bedaquiline alone. Potentiation also extended to pretomanid and other key agents. Disruption of upstream menaquinone and shikimate pathway enzymes produced similar resensitisation, establishing these pathways as tractable targets for restoring drug susceptibility in Mycobacterium tuberculosis. These findings provide a novel strategy to overcome bedaquiline resistance and strengthen future regimens for efflux-mediated drug-resistant tuberculosis.

microbiology↗

bioRxiv2025

Host mRNA 3'-end processing machinery are critical binding partners during dengue virus infection

Dengue virus (DENV) causes a wide variety of dengue diseases that threaten over half of the worlds population. At present, there is no antiviral therapeutics against dengue. Virus infection and its associated pathologies are the result of a myriad of interactions between the virus and its host, of which most are protein-protein interactions (PPIs). Virus-encoded proteins modulate the host environment for the virus benefit by interacting with host proteins during infection. Thus studies of these virus-host PPIs are most informative when performed in the context of an infection. We undertook a comparative affinity purification-mass spectrometry approach to generate a DENV-host protein-protein interactome during DENV infection and identified mRNA 3-end processing protein complexes as novel interactors of DENV NS3. We demonstrated that the presence of the cleavage and polyadenylation specificity factor complex proteins, but not their enzymatic activity, is crucial for DENV replication, thus unveiling a potential new direction for the development of host-directed antiviral therapeutics.

microbiology↗

bioRxiv2021

Antibody response patterns to Helicobacter pylori infection in a rural Ugandan population cohort.

BackgroundHelicobacter pylori (H. pylori) establishes life-long infection in humans in the absence of treatment and has been associated with a variety of gastrointestinal conditions including peptic ulcer and gastric cancer. Antibody responses to H. pylori antigens are found to be associated with disease risk, however, data from Africa are scarce. MethodsTo assess the seroprevalence of H. pylori and characterise antibody response patterns, we measured serum IgG antibody levels to 14 antigens among 7,211 individuals in a rural Ugandan population cohort. Multivariate-adjusted linear regression models were fitted to investigate the influence of age, sex, and co-infection on antibody seroreactivity levels. ResultsH. pylori seroprevalence was 95% in our study population, with 94% of individuals seropositive in childhood (<15 years). In H. pylori positive individuals, we found a markedly high seroprevalence (~99%) and antibody levels to the high-risk antigens CagA and VacA, in addition to Cag{delta}. HSV-2 co-infection was significantly associated with higher IgG levels of CagA and VacA (OR=1.10, 95% C. I=1.05-1.16). HIV infection was associated with lowered IgG levels to CagA (OR=0.86, 95% C.I.=0.80-0.93), and HPV infection was associated with increased IgG levels to VacA (OR=1.16, 95% C.I.=1.11-1.21). ConclusionsH. pylori in this population is ubiquitous from childhood, with a high prevalence and high seroreactivity levels of high-risk antigens, suggesting chronic active inflammatory responses in individuals that are indicative of risk of disease. Further investigation is warranted to fully understand the relationship between host, immunogenicity, and clinical outcomes to better stratify by risk and improve treatment. Key MessagesO_LIAntibody responses to H. pylori antigens are found to be associated with risk of gastric cancer, however, despite the high seroprevalence in African populations, data from Africa are scarce. This is the first study of antibody response patterns and their determinants from an African population. C_LIO_LIOur study shows a population where H. pylori is ubiquitous from childhood, and seroprevalence of virulent antigens is distinctively high suggesting an increased of disease compared to other populations. C_LIO_LIWe observe inter-individual variation in virulent antibody responses partly influenced by co-infection. C_LIO_LIWe highlight crucial insights into antibody-based biomarkers of disease risk and reinforce the need for population-based H. pylori screening and treatment programmes for gastric cancer control. C_LI

immunology↗

bioRxiv2020

An integrated in silico immuno-genetic analytical platform provides insights into COVID-19 serological and vaccine targets

BackgroundThe COVID-19 pandemic, caused by the SARS-CoV-2 virus, has a major global health and socio-economic burden. It has instigated the mobilisation of resources into the development of control tools, such as diagnostics and vaccines. The poor performance of some diagnostic serological tools has emphasised the need for up to date immune-informatic analyses to inform the selection of viable targets for further study. This requires the integration and analysis of genetic and immunological data for SARS-CoV-2 and its homology with other human coronavirus species to understand cross-reactivity. MethodsWe have developed an online "immuno-analytics" resource to facilitate SARS-CoV-2 research, combining an extensive B/T-cell epitope mapping and prediction meta-analysis, and human CoV sequence homology mapping and protein database annotation, with an updated variant database and geospatial tracking for >7,800 non-synonymous mutation positions derived from >150,000 whole genome sequences. To demonstrate its utility, we present an integrated analysis of SARS-CoV-2 spike and nucleocapsid proteins, both being vaccine and serological diagnostic targets, including an analysis of changes in relevant mutation frequencies over time. ResultsOur analysis reveals that the nucleocapsid protein in its native form appears to be a sub-optimal target for use in serological diagnostic platforms. The most frequent mutations were the spike protein D614G and nsp12 L314P, which were common (>86%) across all the geographical regions. Some mutations in the spike protein (e.g. A222V and L18F) have increased in frequency in Europe during the latter half of 2020, detected using our automated algorithms. The tool also suggests that orf3a proteins may be a suitable alternative target for diagnostic serologic assays in a post-vaccine surveillance setting. ConclusionsThe immuno-analytics tool can be accessed online (http://genomics.lshtm.ac.uk/immuno) and will serve as a useful resource for biological discovery and surveillance in the fight against SARS-CoV-2. Further, the tool may be adapted to inform on biological targets in future outbreaks, including potential emerging human coronaviruses that spill over from animal hosts.

bioinformatics↗

bioRxiv2020

Controlling the SARS-CoV-2 outbreak, insights from large scale whole genome sequences generated across the world

BackgroundSARS-CoV-2 most likely evolved from a bat beta-coronavirus and started infecting humans in December 2019. Since then it has rapidly infected people around the world, with more than 4.5 million confirmed cases by the middle of May 2020. Early genome sequencing of the virus has enabled the development of molecular diagnostics and the commencement of therapy and vaccine development. The analysis of the early sequences showed relatively few evolutionary selection pressures. However, with the rapid worldwide expansion into diverse human populations, significant genetic variations are becoming increasingly likely. The current limitations on social movement between countries also offers the opportunity for these viral variants to become distinct strains with potential implications for diagnostics, therapies and vaccines. MethodsWe used the current sequencing archives (NCBI and GISAID) to investigate 15,487 whole genomes, looking for evidence of strain diversification and selective pressure. ResultsWe used 6,294 SNPs to build a phylogenetic tree of SARS-CoV-2 diversity and noted strong evidence for the existence of two major clades and six sub-clades, unevenly distributed across the world. We also noted that convergent evolution has potentially occurred across several locations in the genome, showing selection pressures, including on the spike glycoprotein where we noted a potentially critical mutation that could affect its binding to the ACE2 receptor. We also report on mutations that could prevent current molecular diagnostics from detecting some of the sub-clades. ConclusionThe worldwide whole genome sequencing effort is revealing the challenge of developing SARS-CoV-2 containment tools suitable for everyone and the need for data to be continually evaluated to ensure accuracy in outbreak estimations.

genomics↗

bioRxiv2019

Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification

Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate the development of diagnostic tests.\n\nTo identify minimal transcript signatures, we applied a novel transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were validated using reverse transcriptase (RT) - digital PCR (dPCR).\n\nA four-transcript signature (GBP6, TMCC1, PRDM1, ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2 - 100%). A three-transcript signature (FCGR1A, ZNF296, C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3 - 100%), regardless of HIV.\n\nThese signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.

molecular biology↗