Biology subjects

Balmer, A. J.

Publications and source records attributed to Balmer, A. J..

7 recordsLinked to original sources

bioRxiv2026

Spatial lung niches shape Pseudomonas aeruginosa persistence

Chronic Pseudomonas aeruginosa lung infection is a major cause of morbidity and mortality in people with pre-existing lung disease. Once established, infection is rarely eradicated and often persists despite prolonged antimicrobial therapy, but the underlying mechanisms remain poorly understood. To define how P. aeruginosa occupies and adapts to diseased lung tissue, we applied host-pathogen spatial transcriptomics to profile over 23 million lung cells from explanted and resected lungs from people with Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD), mapping bacterial niches and transcriptional states in situ. We found that P. aeruginosa adopted distinct niche-linked states across chronically infected human lung tissue. Bacterial burden was highest in airway lumens, but bacteria also occupied submucosal glands, parenchyma and, unexpectedly, blood vessel lumens in CF tissue. Within airway lumens, two coupled host-pathogen states emerged: an alginate-rich biofilm-like state linked to PI3-positive neutrophil inflammation and host chemical-sensing programmes; and a motile, quorum-sensing state with activated type 6 secretion linked to human ciliary stress, epithelial remodelling and proteolytic injury. Intravascular bacteria co-localised with neutrophils, fibrin and vascular-remodelling signatures, suggesting local breach of barrier integrity and subsequent immune containment. P. aeruginosa also displayed disease-specific cellular associations, with neutrophil-dominated interactions in CF and greater association with macrophages and dendritic cells in COPD. Together, these data reveal chronic P. aeruginosa infection as a spatially partitioned ecosystem in which anatomical microenvironments impose distinct bacterial lifestyles and host inflammatory states. This niche-resolved framework helps explain how persistent infection can diversify within a single lung and suggests that eradication therapies may need to target multiple anatomical and cellular niches to be effective.

immunology↗

bioRxiv2025

Pf-PeptideFilter: An Interactive Catalogue of Peptide Vaccine Candidates for Plasmodium falciparum

In the last decade, there has been substantial progress in vaccine development for malaria, with two WHO-recommended vaccines now available-RTS,S/AS01 (Mosquirix) and R21/Matrix-M. While these vaccines represent significant milestones, their partial efficacy underscores the need to develop next-generation vaccine approaches capable of broader, longer-lasting protection. Peptide vaccines are a promising strategy, as they focus on short, synthetic peptides specifically selected to trigger a T-cell immune response. However, developing effective peptide vaccines for malaria remains challenging, due to the extensive genetic diversity of Plasmodium falciparum. Currently, tools for comparing and prioritising immunogenic targets remain limited, and existing approaches overlook key factors, including genetic variation, lifecycle-stage expression, and peptide-level properties, each of which are critical for vaccine efficacy. To address these gaps, we developed Pf-PeptideFilter, an interactive web-based application and curated database designed for filtering peptide vaccine targets across the P. falciparum genome. By integrating population-scale genomic information (Pf7), liver-stage transcriptomics, and other biological annotations, Pf-PeptideFilter enables users to interactively filter potential vaccine candidates from the P. falciparum genome, based on several criteria relevant to vaccine design. The app allows users to prioritise candidate genes and peptides with immunogenic potential and export shortlists for incorporation into experimental workflows, offering an interactive platform for rational peptide vaccine design in P. falciparum. Author SummaryMalaria vaccines are challenging to design because the parasite responsible for most infections, Plasmodium falciparum, is highly genetically diverse. If a vaccine targets part of the parasite proteome that varies between strains, it may protect against only a subset of parasites and perform poorly across regions. Peptide vaccines offer a promising approach, by focusing immune responses on short, synthetic peptides selected to trigger T-cell immunity. However, identifying which peptides to include in a vaccine is difficult, as the parasite genome contains thousands of genes and huge numbers of potential peptide targets. Here, we introduce Pf-PeptideFilter, an interactive tool that helps researchers prioritise peptide vaccine candidates using a series of biologically relevant filters. We integrate population-scale genome variation from thousands of parasite samples with information on gene expression during liver infection, similarity to human proteins, and conservation across related parasite species. Users can adjust filtering thresholds and immediately see how these choices affect which genes and peptides are retained. Pf-PeptideFilter generates downloadable shortlists designed to support experimental follow-up, providing a robust and transparent platform for the early stages of vaccine design.

genomics↗

bioRxiv2025

Antimicrobial Resistance Cartography: A Generalisable Framework for Studying Multivariate Drug Resistance

Beta-lactam resistance in Streptococcus pneumoniae is typically analysed one antibiotic at a time, often using resistant/susceptible classifications. This obscures the fact that minimum inhibitory concentrations (MICs) in this species are continuous, vary across beta-lactam subclasses in correlated but non-identical ways, and reflect complex genetic variation in underlying penicillin-binding proteins (PBPs). To address this, we develop a framework for analysing multivariate resistance phenotypes, which we term Antimicrobial Resistance Cartography, and apply it to 3,628 invasive pneumococcal isolates from the U.S. Active Bacterial Core surveillance programme with MICs measured for six beta-lactams. We demonstrate how this approach simplifies visualisation of resistance data across multiple drugs, resolves common issues such as missing or censored values, and identifies genetic mutations driving correlated resistance changes across multiple beta-lactam antibiotics. We characterise penicillin-binding protein (PBP) substitutions associated with increases in minimum inhibitory concentration to beta-lactam subclasses, revealing subtle differences in their correlated phenotypic effects, and identifying potential constraints on resistance evolution across genetic backgrounds. Moreover, we find pneumococcal lineages harbour distinct combinations of PBP substitutions which give rise to lineage-specific multivariate resistance profiles. Together, these results establish a multivariate view of pneumococcal beta-lactam resistance, revealing how combinations of PBP substitutions work together to generate distinct resistance phenotypes across related antibiotics.

genomics↗

bioRxiv2025

Emergence of zoonotic and multi-drug resistant Streptococcus suis

BackgroundStreptococcus suis is an emerging zoonotic porcine pathogen and a leading cause of adult bacterial meningitis in Southeast Asia, associated with raw pork consumption. Most zoonotic S. suis infections globally are by strains from lineage CC1 carrying a serotype 2 capsule. However, in Thailand, [~]40% of the reported zoonotic infections are caused by two endemic lineages, CC104 and CC233 which also have a serotype 2 capsule. In this study, we aimed to identify the drivers of the emergence and recent evolution of these two lineages. MethodsWe sequenced the whole genomes of 141 Thai S. suis zoonotic and porcine strains isolated over a 15-year period and combined them with a curated global dataset of 2761 published S. suis genomes. Using comparative genomics, Bayesian evolutionary models and multivariate analysis we investigated the emergence of zoonotic potential and multi-drug resistance in CC104 and CC233. FindingsWe estimated recent emergence dates for both CC104 (1990; 95% posterior: 1987-1992) and CC233 (2002; 95% posterior: 2000-2004). Both lineages acquired a serotype capsule 2 from CC1 through a capsule locus switching event, prior to their emergence. Both have also experienced multiple antimicrobial resistance (AMR) acquisition events, with some strains carrying 12 determinants encoding resistance against eight classes of antibiotics. Most importantly, CC104 and CC233 lineages are the first zoonotic lineages to have acquired increased resistance to penicillin and ceftriaxone, which form the standard therapy to treat S. suis infections in humans. InterpretationHorizontal transfer of multiple genomic regions can cause rapid emergence of novel multi-drug-resistant zoonotic S. suis lineages. As S. suis is mainly controlled and treated through the use of antibiotics in both pigs and humans, these findings highlight the urgent need for improved and enhanced surveillance, infection control, and treatments.

microbiology↗

bioRxiv2024

Understanding the Global Spread of Artemisinin Resistance: Insights from over 100K Plasmodium falciparum Samples

Artemisinin partial resistance (ART-R) in Plasmodium falciparum is one of the most pressing threats to global malaria control. Over the last two decades, ART-R has spread widely across Southeast Asia, compromising public health strategies and hindering elimination efforts. As of 2024, ART-R has now emerged in East Africa, with the potential to dramatically increase human mortality in the region. Mitigating the spread of ART-R requires detailed genomic surveillance of point mutations in the kelch13 gene, the primary determinant of resistance to artemisinin derivatives. Although extensive surveillance data on these markers is available, it is distributed across many literature studies and open databases. In this literature review, we aggregate publicly available spatiotemporal data for 112,933 P. falciparum samples between 1980 - 2023 into a single resource, providing the most comprehensive overview of kelch13 markers to date. By synthesising insights from these samples over a global scale, we outline the history and current status of kelch13 mutations associated with ART-R, with particular reference to their emergence in Southeast Asia and recent emergence in East and Northeast Africa. Concerningly, we find their recent increases in frequency in these areas of Africa are comparable to those observed in Southeast Asia 10-15 years ago. We review several factors that may influence the spread of ART-R going forwards, such as fitness costs, treatment strategies, and local epidemiological dynamics, before articulating possible scenarios on how resistance may spread in Africa in coming years. In summary, this review provides a unified, comprehensive account of how the situation of ART-R has unfolded globally so far, highlighting insights both for researchers in the field and public health bodies which aim to reduce its negative effects. More broadly, we highlight the critical role genomic surveillance has had, and will continue to have in combating the spread of ART-R.

genomics↗

bioRxiv2023

The emergence and diversification of a zoonotic pathogen from within the microbiota of intensively farmed pigs

The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species this can affect the health of humans as well as livestock. Here we investigate how livestock microbiota can act as a source of these emerging pathogens through analysis of Streptococcus suis, a ubiquitous component of the respiratory microbiota of pigs that is also a major cause of disease on pig farms and an important zoonotic pathogen. Combining molecular dating, phylogeography and comparative genomic analyses of a large collection of isolates, we find that several pathogenic lineages of S. suis emerged in the 19th and 20th centuries, during an early period of growth in pig farming. These lineages have since spread between countries and continents, mirroring trade in live pigs. They are distinguished by the presence of three genomic islands with putative roles in metabolism and cell adhesion, and an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology. Reconstructions of the evolutionary histories of these islands reveal constraints on pathogen emergence that could inform control strategies, with pathogenic lineages consistently emerging from one subpopulation of S. suis and acquiring genes through horizontal transfer from other pathogenic lineages. These results shed light on the capacity of the microbiota to rapidly evolve to exploit changes in their host population and suggest that the impact of changes in farming on the pathogenicity and zoonotic potential of S. suis is yet to be fully realised.

evolutionary biology↗

bioRxiv2021

Mutation rate dynamics reflect ecological changes in an emerging zoonotic pathogen

While mutation is often deleterious, it can also be adaptive. Mutation rates vary both within and between bacterial species, and understanding what drives this variation is essential for understanding the evolutionary dynamics of bacterial populations. In this study we investigate two factors that are predicted to influence the trade-off between the costs and benefits of mutation: ecology and genome size. To investigate the relationship between these factors and mutation rate we conducted mutation accumulation experiments on eight strains of the emerging zoonotic pathogen Streptococcus suis. Natural variation within this species allows us to compare tonsil carriage and invasive disease isolates, from both more and less pathogenic populations, with a wide range of genome sizes. We find that invasive disease isolates have repeatedly evolved mutation rates that are higher than those of closely related carriage isolates, regardless of variation in genome size. Independent of this variation in overall rate, we also observe a stronger bias towards G/C to A/T mutations in isolates from more pathogenic populations, whose genomes tend to be smaller and more AT-rich. Our results suggest that ecology is a stronger correlate of mutation rate than genome size over these timescales, and that transitions to invasive disease are consistently accompanied by rapid increases in mutation rate. These results shed light on the impact ecology can have on the adaptive potential of bacterial pathogens.

evolutionary biology↗