Biology subjects

Keating, D.

Publications and source records attributed to Keating, D..

6 recordsLinked to original sources

bioRxiv2025

From colonisation to chronicity: adaptation of Mycobacterium abscessus in the cystic fibrosis lung environment

Chronic infection by opportunistic pathogens is a major contributor to mortality in people with cystic fibrosis (CF). These infections are caused by antimicrobial resistant (AMR) pathogens such as the emerging pathogen, Mycobacterium abscessus, a nontuberculous mycobacteria (NTM) which causes recalcitrant infections with high resistance to antibiotics. M. abscessus adapts over time of colonisation to the conditions in the CF lung, hampering effective treatment. The mechanisms underlying this pathoadaptation are poorly understood and are critical for the development of future therapies. Sequential isolate pairs of M. abscessus from three people with CF were examined for adaptive changes over time of infection. Genomic analysis confirmed that these isolate pairs were clonal. The late infection isolates showed increased host cell attachment to CF bronchial epithelial cells and increased intracellular survival in macrophages, indicative of adaptation to the CF lung environment. Late isolates also showed changes in their proteomes, including changes in abundance of proteins with roles in intracellular survival and antibiotic resistance. Overall, it is clear that M. abscessus can adapt to the CF lung environment and improve its ability to interact with host cells. Impact StatementChronic infection by antimicrobial resistant bacteria impacts both the quality of life and mortality in people with CF. We explored the process of adaptation in the emerging pathogen, Mycobacterium abscessus, over the course of a chronic infection in the CF lung. While this process has been well-documented in other opportunistic pathogens which colonise the CF lung, limited data exist on this process in M. abscessus. Phenotype and proteome changes were assessed in sequential longitudinal clinical isolates of M. abscessus obtained from Saint Vincents University Hospital (SVUH), Dublin, Ireland. Significant changes in the interactions with human cells were observed in late infection isolates after as little as 33 days. Understanding these processes may reveal new avenues for clinical exploitation and this study reveals some novel adaptations which could be exploited to aid current therapies.

microbiology↗

bioRxiv2025

Mechanistic insights and clinical implications of cross-reactive anti-prophage antibodies and bacterial heteroresistance on phage therapeutic failure

Phage therapy is an exciting strategy against antimicrobial-resistant bacterial infections, but critical knowledge gaps regarding its clinical application persist. Studying a patient with a life-threatening, chronic bacterial infection who failed phage therapy, we uncovered important biological concepts with direct translational impact. Using longitudinal clinical samples, we found that patients can harbour pre-existing antibodies against active prophages induced from the genome of the causative pathogen. Notably, these antibodies can contribute to clinical failure by cross-reacting with and effectively neutralising therapeutic phage. We also uncovered bacterial heteroresistance, characterised by bacterial subpopulations from the initial infection with reduced phage susceptibility, as a further contributor to treatment failure. These findings highlight the intricate interplay between host immunology, bacterial genetic diversity and phage biology, bearing broad significance for clinical phage therapy. Future phage therapy patients, especially those with chronic infections, should be screened for antiphage immunity and bacterial heteroresistance prior to phage treatment.

microbiology↗

bioRxiv2023

Social and genetic diversity in first farmers of central Europe

The Linearbandkeramik (LBK) Neolithic communities were the first to spread farming across large parts of central Europe, settling fertile regions from Ukraine to France during the second half of the 6th millennium BCE. The LBK had a high degree of material culture uniformity, albeit with regional differences in settlement patterns, subsistence, and mortuary practices. To date, ancient DNA data from LBK individuals have been generated for a limited number of locations and often in small sample sizes, making it challenging to study variation within and across sites. We report genome-wide data for 178 LBK individuals, from the Alfold Linearbankeramik Culture (ALPC) eastern LBK site of Polgar-Ferenci-hat in Hungary, the western LBK site of Nitra in Slovakia, and the enclosed western LBK settlement and massacre site of Schletz in Austria, as well as 42 LBK individuals from 18 other sites. We also report genome-wide data for 28 Early Neolithic Koros and Star[c]evo individuals from 13 sites, viewed as the predecessors of the LBK. We observe a higher percentage of western hunter-gatherer (WHG) admixture among individuals in the eastern LBK than in the far more widely distributed western LBK, showing that these two archaeologically distinct cultures also had different genetic trajectories. Most WHG-farmer mixture occurred just before the dawn of the LBK culture and there is no evidence that the WHG ancestry came systematically more from males or females. However, we do find strong genetic evidence for patrilocality among the LBK, extending previous findings based on isotopic analysis, with more genetic structure across sites on the male than on the female line, and a higher rate of within-site relatives for males. At Schletz we detect almost no first-degree relatives despite reporting data from almost every skeleton present at the site, showing that this massacre involved people from a large population, not a small community.

genetics↗

bioRxiv2018

The genetic prehistory of the Greater Caucasus

Archaeogenetic studies have described the formation of Eurasian steppe ancestry as a mixture of Eastern and Caucasus hunter-gatherers. However, it remains unclear when and where this ancestry arose and whether it was related to a horizon of cultural innovations in the 4th millennium BCE that subsequently facilitated the advance of pastoral societies likely linked to the dispersal of Indo-European languages. To address this, we generated genome-wide SNP data from 45 prehistoric individuals along a 3000-year temporal transect in the North Caucasus. We observe a genetic separation between the groups of the Caucasus and those of the adjacent steppe. The Caucasus groups are genetically similar to contemporaneous populations south of it, suggesting that - unlike today - the Caucasus acted as a bridge rather than an insurmountable barrier to human movement. The steppe groups from Yamnaya and subsequent pastoralist cultures show evidence for previously undetected farmer-related ancestry from different contact zones, while Steppe Maykop individuals harbour additional Upper Palaeolithic Siberian and Native American related ancestry.

genomics↗

bioRxiv2018

The Genomic Formation of South and Central Asia

The genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia--consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC--and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.\n\nOne Sentence SummaryGenome wide ancient DNA from 357 individuals from Central and South Asia sheds new light on the spread of Indo-European languages and parallels between the genetic history of two sub-continents, Europe and South Asia.

genomics↗

bioRxiv2017

Paleo-Eskimo genetic legacy across North America

Paleo-Eskimos were the first people to settle vast regions of the American Arctic around 5,000 years ago, and were subsequently joined and largely displaced around 1,000 years ago by ancestors of the present-day Inuit and Yupik. The genetic relationship between Paleo-Eskimos and Native American populations remains uncertain. We analyze ancient and present-day genome-wide data from the Americas and Siberia, including new data from Alaskan Inupiat and West Siberian populations, and the first genome-wide DNA from ancient Aleutian Islanders, ancient northern Athabaskans, and a 4,250-year-old individual of the Chukotkan Ust'-Belaya culture. Employing new methods based on rare allele and haplotype sharing as well as established methods based on allele frequency correlations, we show that Paleo-Eskimo ancestry is widespread among populations who speak Na-Dene and Eskimo-Aleut languages. Using phylogenetic modelling with allele frequency correlations and rare variation, we present a comprehensive model for the complex peopling of North America.

genetics↗