Biology subjects

McDonald, R. A.

Publications and source records attributed to McDonald, R. A..

5 recordsLinked to original sources

bioRxiv2025

Alveolar metabolite availability facilitates secondary infection by Pseudomonas aeruginosa in acutely injured lungs

Secondary bacterial pneumonia is a frequent complication of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Prior efforts to explain increased pneumonia risk in ALI/ARDS have focused on impaired immunity and bacterial virulence, but have overlooked the potential contribution of ecological factors within acutely injured lungs. Here, we show that lung injury profoundly alters the alveolar metabolic microenvironment, a change that can be exploited by a common pneumonia pathogen. In mice and humans, we found that growth of Pseudomonas aeruginosa (the most prominent respiratory pathogen in a retrospective cohort of patients with ARDS) is enhanced by increased alveolar concentrations of multiple ALI/ARDS-associated metabolites, which are derived from the blood and cross the compromised alveolar-capillary barrier during alveolar leak. Collectively, this work reveals an ecological mechanism by which pathogens may survive in the injured lung microenvironment and identifies new potential targets for secondary pneumonia prevention and treatment.

microbiology↗

bioRxiv2024

Detecting superspreaders in wildlife reservoirs of disease

Bovine tuberculosis (bTB) has significant socio-economic and welfare impacts on the cattle industry worldwide. In the United Kingdom and Ireland, disease control is complicated by the presence of infection in wildlife, principally the European badger. Control strategies tend to be applied to whole populations, but better-targeted management of key sources of transmission, be they individuals or groups, may be more efficient. Mechanistic transmission models can be used to better understand key epidemiological drivers of disease spread and identify high-risk individuals and groups as long as they can be adequately fitted to observed data. However, this is a significant challenge, especially within wildlife populations, because monitoring relies on imperfect diagnostic test information, and even under systematic surveillance efforts (such as capture-mark-recapture sampling) epidemiological events are only partially observed. To this end we develop a stochastic compartmental model of bTB transmission, and fit this to individual-level data from a unique > 40-year longitudinal study of 2,391 badgers using a recently developed individual forward filtering backward sampling algorithm. Modelling challenges are further compounded by spatio-temporal meta-population structures and age-dependent mortality. We develop a novel estimator for the individual effective reproduction number that provides quantitative evidence for the presence of superspreader badgers, despite the population-level effective reproduction number being less than one. We also infer measures of the hidden burden of infection in the host population through time; the relative likelihoods of competing routes of transmission; effective and realised infectious periods; and longitudinal measures of diagnostic test performance. This modelling framework provides an efficient and generalisable way to fit state-space models to individual-level data in wildlife populations, which allows identification of high-risk individuals and exploration of important epidemiological questions about bTB and other wildlife diseases. Author summaryWild animals commonly harbour infectious diseases with risk of spillover to humans and livestock. We fitted an individual-level stochastic spatial meta-population model of bovine tuberculosis (bTB) transmission to data from a long-term longitudinal study of the European badger (Meles meles). Our framework provides an efficient and generalisable means of fitting state-space models to individual-level data, to identify high-risk individuals and explore important epidemiological questions. We develop a novel estimator for the individual effective reproduction number, providing quantitative evidence for the presence of superspreader badgers (those individuals most responsible for onward transmission of infection), despite the population-level effective reproduction number being less than one. Predicting the hidden burden of infection in individuals and social groups is critical for disease management but challenging in practice, since monitoring relies on imperfect surveillance and diagnostic testing, however control of bTB in badgers could be substantially increased by targeting interventions at high-risk groups.

ecology↗

bioRxiv2020

Application of an ecology-based analytic approach to discriminate signal and noise in low-biomass microbiome studies: whole lung tissue is the preferred sampling method for amplicon-based characterization of murine lung microbiota

BackgroundLow-biomass microbiome studies (such as those of the lungs, placenta, and skin) are vulnerable to contamination and sequencing stochasticity, which obscure legitimate microbial signal. Since low-biomass microbiome fields have had variable success in establishing the reality and clinical significance of identified microbiota, we sought to develop and apply an analytical approach to discriminate signal from noise in low-biomass microbiome studies. We used this approach to determine the optimal sampling strategy in murine lung microbiome studies, which will be essential for future mechanistic lung microbiome research. MethodsUsing a novel, ecology-based analytic approach, we compared bacterial DNA from the lungs of healthy adult mice collected via two common sampling approaches: homogenized whole lung tissue and bronchoalveolar lavage (BAL) fluid. We quantified bacterial DNA using droplet digital PCR, characterized bacterial communities using 16S rRNA gene sequencing, and systematically assessed the quantity and identity of bacterial DNA in both specimen types. We compared bacteria detected in lung specimens to each other and to potential source communities: negative (background) control specimens and paired oral samples. FindingsBy all measures, whole lung tissue in mice contained greater bacterial signal and less evidence of contamination than did BAL fluid. Relative to BAL fluid, whole lung tissue exhibited a greater quantity of bacterial DNA, distinct community composition, decreased sample-to-sample variation, and greater biological plausibility when compared to potential source communities. In contrast, bacteria detected in BAL fluid were minimally different from those of procedural, reagent, and sequencing controls. InterpretationAn ecology-based analytical approach discriminates signal from noise in low-biomass microbiome studies and identifies whole lung tissue as the preferred specimen type for murine lung microbiome studies. Sequencing, analysis, and reporting of potential source communities, including negative control specimens and contiguous biological sites, is crucial for biological interpretation of low-biomass microbiome studies, independent of specimen type. FundingNational Institutes of Health

microbiology↗

bioRxiv2020

Ecology of domestic dogs Canis familiaris as an emerging reservoir of Guinea worm Dracunculus medinensis infection

Global eradication of human Guinea worm disease (dracunculiasis) has been set back by the emergence of infections in animals, particularly domestic dogs Canis familiaris. The ecology and epidemiology of this reservoir is unknown. We tracked dogs using GPS, inferred diets using stable isotope analysis and analysed correlates of infection in Chad, where numbers of Guinea worm infections are greatest. Dogs had small ranges that varied markedly among villages. Diets consisted largely of human staples and human faeces. A minority of ponds, mostly <200 m from dog-owning households, accounted for most dog exposure to potentially unsafe water. The risk of a dog having had Guinea worm was reduced in dogs living in households providing water for animals but increased with increasing fish consumption by dogs. Provision of safe water might reduce dog exposure to unsafe water, while prioritisation of proactive temephos (Abate) application to the small number of ponds to which dogs have most access is recommended. Fish might have an additional role as transport hosts for Guinea worm, by concentrating copepods infected with worm larvae. Author summaryGuinea worm is a parasite that causes profoundly debilitating disease in humans. An eradication program has been successful in nearly eliminating the disease from people. However, the same worm has now been found in domestic dogs and the frequency of detecting Guinea worm in dogs has been increasing. This means that to eradicate Guinea worm, the infection must be eliminated in dogs as well as in people. However, not much is known about the disease in dogs. This study is the first to investigate dog ecology in relation to Guinea worm infection. We worked in the worst-affected country, Chad. We attached GPS collars to dogs to track their ranging and use of water bodies and analysed their diets using a forensic technique, based on analysing stable isotope compostion of their whiskers and potential food items. We showed that dogs living in households that provided water to their animals had a lower risk of having had Guinea worm and that dogs that ate more fish had an increased risk. These findings suggest there is a classical route for worm transmission in dogs, via drinking contaminated water, as well as a novel route, potentially by eating fish carrying a source of infection.

ecology↗

bioRxiv2017

Estimating Wildlife Vaccination Coverage Using Genetic Methods

Vaccination is a potentially useful approach for the control of disease in wildlife populations. The effectiveness of vaccination is contingent in part on obtaining adequate vaccine coverage at the population level. However, measuring vaccine coverage in wild animal populations is challenging and so there is a need to develop robust approaches to estimate coverage and so contribute to understanding the likely efficacy of vaccination.\n\nWe used a modified capture mark recapture technique to estimate vaccine coverage in a wild population of European badgers (Meles meles) vaccinated by live-trapping and injecting with Bacillus Calmette-Guerin as part of a bovine tuberculosis control initiative in Wales, United Kingdom. Our approach used genetic matching of vaccinated animals to a sample of the wider population to estimate the percentage of badgers that had been vaccinated. Individual-specific genetic profiles were obtained using microsatellite genotyping of hair samples which were collected both directly from trapped and vaccinated badgers and non-invasively from the wider population using hair traps deployed at badger burrows.\n\nWe estimated the percentage of badgers vaccinated in a single year and applied this to a simple model to estimate cumulative vaccine coverage over a four year period, corresponding to the total duration of the vaccination campaign.\n\nIn the year of study, we estimated that between 44-65% (95% confidence interval, mean 55%) of the badger population received a vaccine dose. Using the model, we estimated that 70-85% of the total population would have received at least one vaccine dose over the course of the four year vaccination campaign.\n\nThis study represents the first application of this novel approach for measuring vaccine coverage in wildlife. This is also the first attempt at quantifying the level of vaccine coverage achieved by trapping and injecting badgers. The results therefore have specific application to bovine tuberculosis control policy, and the approach is of significance to the wider field of wildlife vaccination.

ecology↗