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2. The Legionella collagen-like protein employs a distinct binding mechanism for the recognition of host glycosaminoglycans

Author

Rehman, Saima, Antonovic, Anna Katarina, McIntire, Ian E., Zheng, Huaixin, Cleaver, Leanne, Baczynska, Maria, Adams, Carlton O., Portlock, Theo, Richardson, Katherine, Shaw, Rosie, Oregioni, Alain, Mastroianni, Giulia, Whittaker, Sara B-M., Kelly, Geoff, Lorenz, Christian D., Fornili, Arianna, Cianciotto, Nicholas P., and Garnett, James A.

Published
2024
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4. Substrate recognition by the Legionella pneumophila Type II Secretion System

Author

Portlock, Theo

Subjects
616.2
Abstract

The bacterial Type II Secretion System (T2SS) is a transmembrane multiprotein assembly that ejects folded protein substrates from the periplasm into the extracellular milieu. These substrates are essential for pathogenesis in humans, animals, and plants. In the intracellular pathogen Legionella pneumophila, the T2SS has been shown to play an important role in evading recognition by the host during infection. Although much is known about the structures of the compositional proteins of the system, recognition and recruitment of substrates for secretion by the system is a poorly understood process. Previous studies have demonstrated binding between the inner membrane protein XcpPGspC and T2SS substrates in Pseudomonas aeruginosa thus implicating its involvement in this process. In this thesis, the periplasmic linker region of the L. pneumophila homologue of XcpPGspC (LspCGspC) and the T2SS substrate Novel Type II secreted protein A (NttA) (13 kDa) were recombinantly expressed and puri ed in Escherichia coli. Using NMR spectroscopy titration experiments, a weak fast-exchange interaction between these two proteins was observed, showing similar a nities to that previously demonstrated in the study in P. aeruginosa. Solution structures of the two proteins were then solved by NMR spectroscopy. Then, through the computational docking of these two proteins and guided by NMR titration data, a recognition complex was characterised revealing residues essential in the binding process. This is the rst discovered structure of a recognition complex between the T2SS and its substrates in L. pneumophila. This study suggests a novel pharmacophore model that may be used in antibiotic drug design of inhibitors to the formation of the recognition complex.

Published
2020

5. Early life microbial succession in the gut follows common patterns in humans across the globe.

Author

Fahur Bottino, Guilherme, Bonham, Kevin S., Patel, Fadheela, McCann, Shelley, Zieff, Michal, Naspolini, Nathalia, Ho, Daniel, Portlock, Theo, Joos, Raphaela, Midani, Firas S., Schüroff, Paulo, Das, Anubhav, Shennon, Inoli, Wilson, Brooke C., O'Sullivan, Justin M., Britton, Robert A., Murray, Deirdre M., Kiely, Mairead E., Taddei, Carla R., and Beltrão-Braga, Patrícia C. B.

Subjects
STANDARD deviations, LIFE sciences, MICROBIAL genes, MICROORGANISMS, CHILD development
Abstract

Characterizing the dynamics of microbial community succession in the infant gut microbiome is crucial for understanding child health and development, but no normative model currently exists. Here, we estimate child age using gut microbial taxonomic relative abundances from metagenomes, with high temporal resolution (±3 months) for the first 1.5 years of life. Using 3154 samples from 1827 infants across 12 countries, we trained a random forest model, achieving a root mean square error of 2.56 months. We identified key taxonomic predictors of age, including declines in Bifidobacterium spp. and increases in Faecalibacterium prausnitzii and Lachnospiraceae. Microbial succession patterns are conserved across infants from diverse human populations, suggesting universal developmental trajectories. Functional analysis confirmed trends in key microbial genes involved in feeding transitions and dietary exposures. This model provides a normative benchmark of "microbiome age" for assessing early gut maturation that may be used alongside other measures of child development. Here, the authors perform a global analysis of over 3000 infant gut samples revealing a universal pattern of microbial changes over the first 1.5 years, with declines in Bifidobacterium and increases in Faecalibacterium, providing a standard for early gut development. [ABSTRACT FROM AUTHOR]

Published
2025
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7. OS-070 Faecal microbiota transplantation in patients with cirrhosis, reduces antimicrobial resistance and enteric pathogen carriage, and enhances intestinal barrier function, associated with bacteriophage remodelling

Author

Edwards, Lindsey, primary, Auch, Benjamin, additional, Portlock, Theo, additional, Mullish, Benjamin H., additional, Merrick, Blair, additional, Woodhouse, Charlotte, additional, Tranah, Thomas, additional, Blanco, Jesus Miguens, additional, Meoli, Lilianeleny, additional, Llavall, Anna Clavé, additional, Kronsten, Victoria, additional, Zamalloa, Ane, additional, Patel, Vishal C., additional, Marchesi, Julian R., additional, Shoaie, Saeed, additional, Liachko, Ivan, additional, Goldenberg, Simon, additional, and Shawcross, Debbie L., additional

Published
2024
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9. Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbab le, gut-restricted adsorbent in models and patients with cirrhosis

Author

Liu, Jinxia, primary, MacNaughtan, Jane, additional, Kerbert, Annarein J C, additional, Portlock, Theo, additional, Martínez Gonzalez, Javier, additional, Jin, Yi, additional, Clasen, Frederick, additional, Habtesion, Abeba, additional, Ji, Huoyan, additional, Jin, Qin, additional, Phillips, Alexandra, additional, De Chiara, Francesco, additional, Ingavle, Ganesh, additional, Jimenez, Cesar, additional, Zaccherini, Giacomo, additional, Husi, Katherine, additional, Rodriguez Gandia, Miguel Angel, additional, Cordero, Paul, additional, Soeda, Junpei, additional, McConaghy, Lynda, additional, Oben, Jude, additional, Church, Karen, additional, Li, Jia V, additional, Wu, Haifeng, additional, Jalan, Aarti, additional, Gines, Pere, additional, Solà, Elsa, additional, Eaton, Simon, additional, Morgan, Carrie, additional, Kowalski, Michal, additional, Green, Daniel, additional, Gander, Amir, additional, Edwards, Lindsey A, additional, Cox, I Jane, additional, Cortez-Pinto, Helena, additional, Avery, Thomas, additional, Wiest, Reiner, additional, Durand, Francois, additional, Caraceni, Paolo, additional, Elosua, Roberto, additional, Vila, Joan, additional, Pavesi, Marco, additional, Arroyo, Vicente, additional, Davies, Nathan, additional, Mookerjee, Rajeshwar P, additional, Vargas, Victor, additional, Sandeman, Susan, additional, Mehta, Gautam, additional, Shoaie, Saeed, additional, Marchesi, Julian, additional, Albillos, Agustín, additional, Andreola, Fausto, additional, and Jalan, Rajiv, additional

Published
2024
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10. Global compositional and functional states of the human gut microbiome in health and disease

Author

Lee, Sunjae, Portlock, Theo John, Garcia-Guevara, José Fernando, von Feilitzen, Kalle, Johansson, Fredric, Zhang, Cheng, Mardinoglu, Adil, Uhlén, Mathias, Shoaie, Saeed, Lee, Sunjae, Portlock, Theo John, Garcia-Guevara, José Fernando, von Feilitzen, Kalle, Johansson, Fredric, Zhang, Cheng, Mardinoglu, Adil, Uhlén, Mathias, and Shoaie, Saeed

Abstract

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts., QC 20240814

Published
2024
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11. Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

Author

Jinxia Liu, MacNaughtan, Jane, Kerbert, Annarein J. C., Portlock, Theo, Gonzalez, Javier Martínez, Yi Jin, Clasen, Frederick, Habtesion, Abeba, Huoyan Ji, Qin Jin, Phillips, Alexandra, De Chiara, Francesco, Ingavle, Ganesh, Jimenez, Cesar, Zaccherini, Giacomo, Husi, Katherine, Rodriguez Gandia, Miguel Angel, Cordero, Paul, Soeda, Junpei, and McConaghy, Lynda

Subjects
HEPATORENAL syndrome, DIABETIC nephropathies, BETAINE, CIRRHOSIS of the liver, VITAMIN E, ANIMAL tracks, MEDICAL sciences
Published
2024
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12. TheLegionellacollagen-like protein employs a unique binding mechanism for the recognition of host glycosaminoglycans

Author

Rehman, Saima, primary, Antonovic, Anna K., additional, McIntire, Ian E., additional, Zheng, Huaixin, additional, Cleaver, Leanne, additional, Adams, Carlton O., additional, Portlock, Theo, additional, Richardson, Katherine, additional, Shaw, Rosie, additional, Oregioni, Alain, additional, Mastroianni, Giulia, additional, Whittaker, Sara B-M, additional, Kelly, Geoff, additional, Fornili, Arianna, additional, Cianciotto, Nicholas P., additional, and Garnett, James A., additional

Published
2023
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13. Faecal microbiota transplant restores gut barrier function and augments ammonia metabolism in patients with advanced cirrhosis: a randomised single-blind placebo-controlled trial

Author

Edwards, Lindsey A, primary, Woodhouse, Charlotte, additional, Lee, Sunjae, additional, Mullish, Benjamin H., additional, Portlock, Theo, additional, Meoli, Lilianeleny, additional, Kronsten, Victoria, additional, Marchesi, Julian, additional, Zamalloa, Ane, additional, Tranah, Thomas, additional, Patel, Vishal, additional, Shoaie, Saeed, additional, Goldenberg, Simon, additional, and Shawcross, Debbie L., additional

Published
2023
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14. Faecal microbiota transplant restores gut barrier function and augments ammonia metabolism in patients with advanced cirrhosis : a randomised single-blind placebo-controlled trial

Author

Edwards, Lindsey A., Woodhouse, Charlotte, Lee, Sunjae, Mullish, Benjamin H., Portlock, Theo, Meoli, Lilianeleny, Kronsten, Victoria, Marchesi, Julian, Zamalloa, Ane, Tranah, Thomas, Patel, Vishal, Shoaie, Saeed, Goldenberg, Simon, Shawcross, Debbie L., Edwards, Lindsey A., Woodhouse, Charlotte, Lee, Sunjae, Mullish, Benjamin H., Portlock, Theo, Meoli, Lilianeleny, Kronsten, Victoria, Marchesi, Julian, Zamalloa, Ane, Tranah, Thomas, Patel, Vishal, Shoaie, Saeed, Goldenberg, Simon, and Shawcross, Debbie L.

Abstract

QC 20231030

Published
2023

15. Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis

Author

Liu, Jinxia, MacNaughtan, Jane, Kerbert, Annarein J C, Portlock, Theo, Martínez Gonzalez, Javier, Jin, Yi, Clasen, Frederick, Habtesion, Abeba, Ji, Huoyan, Jin, Qin, Phillips, Alexandra, De Chiara, Francesco, Ingavle, Ganesh, Jimenez, Cesar, Zaccherini, Giacomo, Husi, Katherine, Rodriguez Gandia, Miguel Angel, Cordero, Paul, Soeda, Junpei, McConaghy, Lynda, Oben, Jude, Church, Karen, Li, Jia V, Wu, Haifeng, Jalan, Aarti, Gines, Pere, Solà, Elsa, Eaton, Simon, Morgan, Carrie, Kowalski, Michal, Green, Daniel, Gander, Amir, Edwards, Lindsey A, Cox, I Jane, Cortez-Pinto, Helena, Avery, Thomas, Wiest, Reiner, Durand, Francois, Caraceni, Paolo, Elosua, Roberto, Vila, Joan, Pavesi, Marco, Arroyo, Vicente, Davies, Nathan, Mookerjee, Rajeshwar P, Vargas, Victor, Sandeman, Susan, Mehta, Gautam, Shoaie, Saeed, Marchesi, Julian, Albillos, Agustín, Andreola, Fausto, and Jalan, Rajiv

Abstract

ObjectiveTargeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis.DesignPerformance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed.ResultsYaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial.ConclusionsThis study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation.Trial registration numberNCT03202498.

Published
2024
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17. Multi-omics analyses reveal multimodal Fusobacterium DNA damage perturbations in colorectal cancer

Author

Kataria, Radhika, primary, Quist, Jelmar, additional, Lee, Sunjae, additional, Megalios, Anargyros, additional, Sawyer, Elinor, additional, Hardiman, Thomas, additional, Liu, Chang, additional, Kelly, Katherine, additional, Portlock, Theo, additional, Alon-Maimon, Tamar, additional, Wan, Jonathan, additional, Bachrach, Gilad, additional, Shoaie, Saeed, additional, and Grigoriadis, Anita, additional

Published
2022
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21. Structure, Dynamics and Cellular Insight Into Novel Substrates of the Legionella pneumophila Type II Secretion System

Author

Portlock, Theo J., primary, Tyson, Jessica Y., additional, Dantu, Sarath C., additional, Rehman, Saima, additional, White, Richard C., additional, McIntire, Ian E., additional, Sewell, Lee, additional, Richardson, Katherine, additional, Shaw, Rosie, additional, Pandini, Alessandro, additional, Cianciotto, Nicholas P., additional, and Garnett, James A., additional

Published
2020
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22. Structure and functional analysis of the Legionella pneumophila chitinase ChiA reveals a novel mechanism of metal-dependent mucin degradation

Author

Rehman, Saima, primary, Grigoryeva, Lubov S., additional, Richardson, Katherine H., additional, Corsini, Paula, additional, White, Richard C., additional, Shaw, Rosie, additional, Portlock, Theo J., additional, Dorgan, Benjamin, additional, Zanjani, Zeinab S., additional, Fornili, Arianna, additional, Cianciotto, Nicholas P., additional, and Garnett, James A., additional

Published
2020
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25. Type II Secretion-Dependent Aminopeptidase LapA and Acyltransferase PlaC Are Redundant for Nutrient Acquisition during Legionella pneumophilaIntracellular Infection of Amoebas

Author

White, Richard C., Gunderson, Felizza F., Tyson, Jessica Y., Richardson, Katherine H., Portlock, Theo J., Garnett, James A., and Cianciotto, Nicholas P.

Abstract

ABSTRACTLegionella pneumophilagenes encoding LapA, LapB, and PlaC were identified as the most highly upregulated type II secretion (T2S) genes during infection of Acanthamoeba castellanii, although these genes had been considered dispensable on the basis of the behavior of mutants lacking either lapAand lapBor plaC. A plaCmutant showed even higher levels of lapAand lapBtranscripts, and a lapA lapBmutant showed heightening of plaCmRNA levels, suggesting that the role of the LapA/B aminopeptidase is compensatory with respect to that of the PlaC acyltransferase. Hence, we made double mutants and found that lapA plaCmutants have an ~50-fold defect during infection of A. castellanii. These data revealed, for the first time, the importance of LapA in any sort of infection; thus, we purified LapA and defined its crystal structure, activation by another T2S-dependent protease (ProA), and broad substrate specificity. When the amoebal infection medium was supplemented with amino acids, the defect of the lapA plaCmutant was reversed, implying that LapA generates amino acids for nutrition. Since the LapA and PlaC data did not fully explain the role of T2S in infection, we identified, via proteomic analysis, a novel secreted protein (NttD) that promotes infection of A. castellanii. A lapA plaC nttDmutant displayed an even greater (100-fold) defect, demonstrating that the LapA, PlaC, and NttD data explain, to a significant degree, the importance of T2S. LapA-, PlaC-, and NttD-like proteins had distinct distribution patterns within and outside the Legionellagenus. LapA was notable for having as its closest homologue an A. castellaniiprotein.IMPORTANCETransmission of L. pneumophilato humans is facilitated by its ability to grow in Acanthamoebaspecies. We previously documented that type II secretion (T2S) promotes L. pneumophilainfection of A. castellanii. Utilizing transcriptional analysis and proteomics, double and triple mutants, and crystal structures, we defined three secreted substrates/effectors that largely clarify the role of T2S during infection of A. castellanii. Particularly interesting are the unique functional overlap between an acyltransferase (PlaC) and aminopeptidase (LapA), the broad substrate specificity and eukaryotic-protein-like character of LapA, and the novelty of NttD. Linking LapA to amino acid acquisition, we defined, for the first time, the importance of secreted aminopeptidases in intracellular infection. Bioinformatic investigation, not previously applied to T2S, revealed that effectors originate from diverse sources and distribute within the Legionellagenus in unique ways. The results of this study represent a major advance in understanding Legionellaecology and pathogenesis, bacterial secretion, and the evolution of intracellular parasitism.

Published
2018
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26. Global compositional and functional states of the human gut microbiome in health and disease.

Author

Lee S, Portlock T, Le Chatelier E, Garcia-Guevara F, Clasen F, Oñate FP, Pons N, Begum N, Harzandi A, Proffitt C, Rosario D, Vaga S, Park J, von Feilitzen K, Johansson F, Zhang C, Edwards LA, Lombard V, Gauthier F, Steves CJ, Gomez-Cabrero D, Henrissat B, Lee D, Engstrand L, Shawcross DL, Proctor G, Almeida M, Nielsen J, Mardinoglu A, Moyes DL, Ehrlich SD, Uhlen M, and Shoaie S

Subjects
Humans, Machine Learning, Fusobacterium nucleatum genetics, Bacteria classification, Bacteria genetics, Gastrointestinal Microbiome genetics, Metagenome, Metagenomics methods
Abstract

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts., (© 2024 Lee et al.; Published by Cold Spring Harbor Laboratory Press.)

Published
2024
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27. The Legionella collagen-like protein employs a unique binding mechanism for the recognition of host glycosaminoglycans.

Author

Rehman S, Antonovic AK, McIntire IE, Zheng H, Cleaver L, Adams CO, Portlock T, Richardson K, Shaw R, Oregioni A, Mastroianni G, Whittaker SB, Kelly G, Fornili A, Cianciotto NP, and Garnett JA

Abstract

Bacterial adhesion is a fundamental process which enables colonisation of niche environments and is key for infection. However, in Legionella pneumophila , the causative agent of Legionnaires' disease, these processes are not well understood. The Legionella collagen-like protein (Lcl) is an extracellular peripheral membrane protein that recognises sulphated glycosaminoglycans (GAGs) on the surface of eukaryotic cells, but also stimulates bacterial aggregation in response to divalent cations. Here we report the crystal structure of the Lcl C-terminal domain (Lcl-CTD) and present a model for intact Lcl. Our data reveal that Lcl-CTD forms an unusual dynamic trimer arrangement with a positively charged external surface and a negatively charged solvent exposed internal cavity. Through Molecular Dynamics (MD) simulations, we show how the GAG chondroitin-4-sulphate associates with the Lcl-CTD surface via unique binding modes. Our findings show that Lcl homologs are present across both the Pseudomonadota and Fibrobacterota-Chlorobiota-Bacteroidota phyla and suggest that Lcl may represent a versatile carbohydrate binding mechanism., Competing Interests: Additional information Competing interests. The authors declare no competing interests.

Published
2023
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