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2. Investigation of a novel iron-uptake system and other genomic features in mecC Staphylococcus aureus

Author

Raisen, Claire and Holmes, Mark

Subjects
636.089, Staphylococcus aureus, Iron acquisition, Von Willebrand
Abstract

Staphylococcus aureus (S. aureus) is a significant pathogen that causes a wide variety of disease in humans and animals. Methicillin resistant S. aureus (MRSA) isolates carrying mecC, the gene that confers resistance to the antibiotic, have been isolated from humans but also from diverse animal species covering livestock, domestic and wild animals throughout Europe. Many of the known MRSA mecC isolates have been whole-genome sequenced by our group to gain insight into the evolution and epidemiology of these emerging lineages. For microbes and humans alike, iron is an essential cofactor in many biochemical reactions and S. aureus requires iron for colonisation and subsequent pathogenesis. The success of S. aureus is partly attributed to its ability to exploit the host iron pool. It does this through multiple iron uptake mechanisms, including at least two high-affinity iron scavenging siderophores (staphyloferrins A and B) and an iron-regulated surface determinant (Isd) pathway for haem-iron acquisition. Here I describe the identification of a novel locus encoding a siderophore-like non-ribosomal peptide synthetase (NRPS), directly downstream of the SCCmec insertion site in mecC S. aureus isolates. A homologous region was identified in Streptococcus equi 4047 (S. equi) which encodes a NRPS termed 'equibactin' that is involved in iron acquisition. I have therefore named the NRPS product 'staphylobactin' in MRSA, and the aim of this study was to determine the function of the staphylobactin biosynthesis cluster: is this region involved in iron acquisition and how might it be regulated? Analysis of the prevalence of isolates containing the staphylobactin locus showed it to be present in a large number of mecC strains in our collection but also identified homologues in other staphylococcus isolates. The region is highly conserved in all S. aureus isolates belonging to clonal complex (CC) 130 (broad host range lineage), suggesting that staphylobactin might impact on S. aureus's ability to infect a broad range of host species. The staphylobactin gene cluster contains 14 coding sequences, stbB-F, F1, G-M and O. Bioinformatic analysis results in predictions of domain and gene functions associated with iron acquisition. I hypothesized that staphylobactin might have been acquired to compensate for the lack of another siderophore, such as staphyloferrin B, but the staphyloferrin B biosynthesis cluster and transport is present in nearly all S. aureus strains, ruling out this model. Unlike the equibactin locus, however, the staphylobactin locus lacks a homolog for the iron-dependent regulator eqbA. Instead, expression of this locus appears to be regulated by MntR, a DtxR-like regulator. The staplylobactin gene cluster is flanked by direct repeats which suggest staphylobactin could have been gained by horizontal gene transfer. In order to study the role of the staphylobactin gene cluster, deletion mutants of MntR, the staphylobactin locus and staphyloferrins A and B, were generated using the pIMAY two step gene deletion procedure in the previously un-manipulated mecC S. aureus CC130 strains - a challenging protocol that required significant optimization given the difficulties with manipulating this bacterium. Analysis of the MntR mutant suggests that the staphylobactin operon is regulated by MntR, acting as a positive regulator, in an iron-dependent manner. By RT-PCR, I found that expression of the staphylobactin NRPS genes is increased when cultures are grown in the absence of iron, suggesting an involvement with iron acquisition. Genomic inactivation of the staphyloferrins resulted in a mutant severely incapacitated for growth in serum and transferrin as the sole iron source, and addition of iron reversed this phenotype. However, deletion of staphylobactin alone or in addition to the staphyloferrins, lacked an iron-dependent growth defect, and numerous assays failed to identify a clear role for staphylobactin in iron metabolism. Therefore, further experiments are needed to elucidate the function of this siderophore like NRPS. Analysis of the same sequenced CC130 mecC isolates from our strain collection in which the staphylobactin locus was found, led to the identification of a novel Von Willebrand (vwb) gene. In order to investigate possible reasons for these isolates to infect a wide range of host species, wild-type and vwb deletion mutant strains, along with the novel vwb expressed in lactococcus, were tested using a coagulation assay and were able to clot plasma from a broad range of host species. Thus the specificity of vWbp proteins can be used to infer the host specificity and evolutionary history of the S. aureus strains that harbour them. Although I was unable to generate definitive evidence revealing the biological role for the staphylobactin locus this study has generated valuable tools for further studies and thoroughly tested a number of hypotheses concerning its role in cation metabolism.

Published
2019
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3. Emergence of methicillin resistance predates the clinical use of antibiotics

Author

Larsen, Jesper, Raisen, Claire L., Ba, Xiaoliang, Sadgrove, Nicholas J., Padilla-González, Guillermo F., Simmonds, Monique S. J., Loncaric, Igor, Kerschner, Heidrun, Apfalter, Petra, Hartl, Rainer, Deplano, Ariane, Vandendriessche, Stien, Černá Bolfíková, Barbora, Hulva, Pavel, Arendrup, Maiken C., Hare, Rasmus K., Barnadas, Céline, Stegger, Marc, Sieber, Raphael N., Skov, Robert L., Petersen, Andreas, Angen, Øystein, Rasmussen, Sophie L., Espinosa-Gongora, Carmen, Aarestrup, Frank M., Lindholm, Laura J., Nykäsenoja, Suvi M., Laurent, Frederic, Becker, Karsten, Walther, Birgit, Kehrenberg, Corinna, Cuny, Christiane, Layer, Franziska, Werner, Guido, Witte, Wolfgang, Stamm, Ivonne, Moroni, Paolo, Jørgensen, Hannah J., de Lencastre, Hermínia, Cercenado, Emilia, García-Garrote, Fernando, Börjesson, Stefan, Hæggman, Sara, Perreten, Vincent, Teale, Christopher J., Waller, Andrew S., Pichon, Bruno, Curran, Martin D., Ellington, Matthew J., Welch, John J., Peacock, Sharon J., Seilly, David J., Morgan, Fiona J. E., Parkhill, Julian, Hadjirin, Nazreen F., Lindsay, Jodi A., Holden, Matthew T. G., Edwards, Giles F., Foster, Geoffrey, Paterson, Gavin K., Didelot, Xavier, Holmes, Mark A., Harrison, Ewan M., and Larsen, Anders R.

Published
2022
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5. Colonization and transmission of Staphylococcus aureus in schools: a citizen science project

Author

van Tonder, Andries J., primary, McCullagh, Frances, additional, McKeand, Hanan, additional, Thaw, Sue, additional, Bellis, Katie, additional, Raisen, Claire, additional, Lay, Liz, additional, Aggarwal, Dinesh, additional, Holmes, Mark, additional, Parkhill, Julian, additional, Harrison, Ewan M., additional, Kucharski, Adam, additional, and Conlan, Andrew, additional

Published
2023
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6. High-Throughput Mutagenesis Reveals a Role for Antimicrobial Resistance- and Virulence-Associated Mobile Genetic Elements in Staphylococcus aureus Host Adaptation

Author

Ba, Xiaoliang, primary, Matuszewska, Marta, additional, Kalmar, Lajos, additional, Fan, Jingyan, additional, Zou, Geng, additional, Corander, Desirée, additional, Raisen, Claire L., additional, Li, Shaowen, additional, Li, Lu, additional, Weinert, Lucy A., additional, Tucker, Alexander W., additional, Grant, Andrew J., additional, Zhou, Rui, additional, and Holmes, Mark A., additional

Published
2023
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9. First ‘One-Health’ study on genome-wide comparison of multidrug-resistant Escherichia coli from Human-Animal-Aquaculture-Environment continuum: a collective effort from six institutes of India

Author

Shome, B, primary, Ojha, Rakshit, additional, Mendem, Suresh, additional, Murugesan, Devi, additional, Sivaraman, Gopalakrishna, additional, Sajeev, Sudha, additional, Ghatak, Sandeep, additional, Phukan, Chimanjita, additional, Hazarika, Suranjana Chaliha, additional, Dubal, Zunjar, additional, Ahammad, Shaikh Ziauddin, additional, Shome, Rajeswari, additional, Raisen, Claire, additional, and Holmes, Mark, additional

Published
2021
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10. The zebrafish reference genome sequence and its relationship to the human genome

Author

Howe, Kerstin, Clark, Matthew D., Torroja, Carlos F., Torrance, James, Berthelot, Camille, Muffato, Matthieu, Collins, John E., Humphray, Sean, McLaren, Karen, Matthews, Lucy, McLaren, Stuart, Sealy, Ian, Caccamo, Mario, Churcher, Carol, Scott, Carol, Barrett, Jeffrey C., Koch, Romke, Rauch, Gerd-Jörg, White, Simon, Chow, William, Kilian, Britt, Quintais, Leonor T., Guerra-Assunção, José A., Zhou, Yi, Gu, Yong, Yen, Jennifer, Vogel, Jan-Hinnerk, Eyre, Tina, Redmond, Seth, Banerjee, Ruby, Chi, Jianxiang, Fu, Beiyuan, Langley, Elizabeth, Maguire, Sean F., Laird, Gavin K., Lloyd, David, Kenyon, Emma, Donaldson, Sarah, Sehra, Harminder, Almeida-King, Jeff, Loveland, Jane, Trevanion, Stephen, Jones, Matt, Quail, Mike, Willey, Dave, Hunt, Adrienne, Burton, John, Sims, Sarah, McLay, Kirsten, Plumb, Bob, Davis, Joy, Clee, Chris, Oliver, Karen, Clark, Richard, Riddle, Clare, Eliott, David, Threadgold, Glen, Harden, Glenn, Ware, Darren, Mortimer, Beverly, Kerry, Giselle, Heath, Paul, Phillimore, Benjamin, Tracey, Alan, Corby, Nicole, Dunn, Matthew, Johnson, Christopher, Wood, Jonathan, Clark, Susan, Pelan, Sarah, Griffiths, Guy, Smith, Michelle, Glithero, Rebecca, Howden, Philip, Barker, Nicholas, Stevens, Christopher, Harley, Joanna, Holt, Karen, Panagiotidis, Georgios, Lovell, Jamieson, Beasley, Helen, Henderson, Carl, Gordon, Daria, Auger, Katherine, Wright, Deborah, Collins, Joanna, Raisen, Claire, Dyer, Lauren, Leung, Kenric, Robertson, Lauren, Ambridge, Kirsty, Leongamornlert, Daniel, McGuire, Sarah, Gilderthorp, Ruth, Griffiths, Coline, Manthravadi, Deepa, Nichol, Sarah, Barker, Gary, Whitehead, Siobhan, Kay, Michael, Brown, Jacqueline, Murnane, Clare, Gray, Emma, Humphries, Matthew, Sycamore, Neil, Barker, Darren, Saunders, David, Wallis, Justene, Babbage, Anne, Hammond, Sian, Mashreghi-Mohammadi, Maryam, Barr, Lucy, Martin, Sancha, Wray, Paul, Ellington, Andrew, Matthews, Nicholas, Ellwood, Matthew, Woodmansey, Rebecca, Clark, Graham, Cooper, James, Tromans, Anthony, Grafham, Darren, Skuce, Carl, Pandian, Richard, Andrews, Robert, Harrison, Elliot, Kimberley, Andrew, Garnett, Jane, Fosker, Nigel, Hall, Rebekah, Garner, Patrick, Kelly, Daniel, Bird, Christine, Palmer, Sophie, Gehring, Ines, Berger, Andrea, Dooley, Christopher M., Ersan-Ürün, Zübeyde, Eser, Cigdem, Geiger, Horst, Geisler, Maria, Karotki, Lena, Kirn, Anette, Konantz, Judith, Konantz, Martina, Oberländer, Martina, Rudolph-Geiger, Silke, Teucke, Mathias, Osoegawa, Kazutoyo, Zhu, Baoli, Rapp, Amanda, Widaa, Sara, Langford, Cordelia, Yang, Fengtang, Carter, Nigel P., Harrow, Jennifer, Ning, Zemin, Herrero, Javier, Searle, Steve M. J., Enright, Anton, Geisler, Robert, Plasterk, Ronald H. A., Lee, Charles, Westerfield, Monte, de Jong, Pieter J., Zon, Leonard I., Postlethwait, John H., Nüsslein-Volhard, Christiane, Hubbard, Tim J. P., Crollius, Hugues Roest, Rogers, Jane, and Stemple, Derek L.

Published
2013
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12. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., Holmes, Mark A., Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., and Holmes, Mark A.

Published
2017

13. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

dFAH I&I, dFAH AVR, dI&I I&I-4, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J, Wagenaar, Jaap A, Klunder, Heleen M, Fitzgerald, J Ross, Zadoks, Ruth, Paterson, Gavin K, Torres, Carmen, Waller, Andrew S, Loeffler, Anette, Loncaric, Igor, Hoet, Armando E, Bergström, Karin, De Martino, Luisa, Pomba, Constança, de Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J, Chilvers, Edwin R, de Haas, Carla, van Kessel, Kok, van Strijp, Jos A G, Harrison, Ewan M, Holmes, Mark A, dFAH I&I, dFAH AVR, dI&I I&I-4, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J, Wagenaar, Jaap A, Klunder, Heleen M, Fitzgerald, J Ross, Zadoks, Ruth, Paterson, Gavin K, Torres, Carmen, Waller, Andrew S, Loeffler, Anette, Loncaric, Igor, Hoet, Armando E, Bergström, Karin, De Martino, Luisa, Pomba, Constança, de Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J, Chilvers, Edwin R, de Haas, Carla, van Kessel, Kok, van Strijp, Jos A G, Harrison, Ewan M, and Holmes, Mark A

Published
2017

14. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

MMB, UMC Utrecht, Infection & Immunity, MMB Research line 1, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., Holmes, Mark A., MMB, UMC Utrecht, Infection & Immunity, MMB Research line 1, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., and Holmes, Mark A.

Published
2017

15. Use of purified Clostridium difficile spores of facilitate evaluation of health care disinfection regimens

Author

Lawley, Trevor D., Clare, Simon, Deakin, Laura J., Goulding, David, Yen, Jennifer L., Raisen, Claire, Brandt, Cordelia, Lovell, Jon, Cooke, Fiona, Clark, Taane G., and Dougan, Gordon

Subjects
Clostridium difficile -- Genetic aspects, Clostridium difficile -- Health aspects, Hydrogen peroxide -- Chemical properties, Infection control -- Methods, Oxidizing agents -- Usage, Oxidizing agents -- Environmental aspects, Biological sciences
Abstract

Simple quantitative methods based on purified Clostridium difficile spores and a murine transmission model are described for analyzing health care disinfection regimens. Pure Clostridium difficile spores have facilitated practical methods for analyzing the efficacy of Clostridium difficile spore disinfection regimens and bringing scientific acumen to C. difficile infection control.

Published
2010

16. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

Koop, Gerrit, primary, Vrieling, Manouk, additional, Storisteanu, Daniel M. L., additional, Lok, Laurence S. C., additional, Monie, Tom, additional, van Wigcheren, Glenn, additional, Raisen, Claire, additional, Ba, Xiaoliang, additional, Gleadall, Nicholas, additional, Hadjirin, Nazreen, additional, Timmerman, Arjen J., additional, Wagenaar, Jaap A., additional, Klunder, Heleen M., additional, Fitzgerald, J. Ross, additional, Zadoks, Ruth, additional, Paterson, Gavin K., additional, Torres, Carmen, additional, Waller, Andrew S., additional, Loeffler, Anette, additional, Loncaric, Igor, additional, Hoet, Armando E., additional, Bergström, Karin, additional, De Martino, Luisa, additional, Pomba, Constança, additional, de Lencastre, Hermínia, additional, Ben Slama, Karim, additional, Gharsa, Haythem, additional, Richardson, Emily J., additional, Chilvers, Edwin R., additional, de Haas, Carla, additional, van Kessel, Kok, additional, van Strijp, Jos A. G., additional, Harrison, Ewan M., additional, and Holmes, Mark A., additional

Published
2017
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17. Erratum: Corrigendum: The zebrafish reference genome sequence and its relationship to the human genome

Author

Howe, Kerstin, primary, Clark, Matthew D., additional, Torroja, Carlos F., additional, Torrance, James, additional, Berthelot, Camille, additional, Muffato, Matthieu, additional, Collins, John E., additional, Humphray, Sean, additional, McLaren, Karen, additional, Matthews, Lucy, additional, McLaren, Stuart, additional, Sealy, Ian, additional, Caccamo, Mario, additional, Churcher, Carol, additional, Scott, Carol, additional, Barrett, Jeffrey C., additional, Koch, Romke, additional, Rauch, Gerd-Jörg, additional, White, Simon, additional, Chow, William, additional, Kilian, Britt, additional, Quintais, Leonor T., additional, Guerra-Assunção, José A., additional, Zhou, Yi, additional, Gu, Yong, additional, Yen, Jennifer, additional, Vogel, Jan-Hinnerk, additional, Eyre, Tina, additional, Banerjee, Ruby, additional, Chi, Jianxiang, additional, Fu, Beiyuan, additional, Langley, Elizabeth, additional, Maguire, Sean F., additional, Laird, Gavin, additional, Lloyd, David, additional, Kenyon, Emma, additional, Donaldson, Sarah, additional, Sehra, Harminder, additional, Almeida-King, Jeff, additional, Loveland, Jane, additional, Trevanion, Stephen, additional, Jones, Matt, additional, Quail, Mike, additional, Willey, Dave, additional, Hunt, Adrienne, additional, Burton, John, additional, Sims, Sarah, additional, McLay, Kirsten, additional, Plumb, Bob, additional, Davis, Joy, additional, Clee, Chris, additional, Oliver, Karen, additional, Clark, Richard, additional, Riddle, Clare, additional, Elliott, David, additional, Threadgold, Glen, additional, Harden, Glenn, additional, Ware, Darren, additional, Begum, Sharmin, additional, Mortimore, Beverley, additional, Kerry, Giselle, additional, Heath, Paul, additional, Phillimore, Benjamin, additional, Tracey, Alan, additional, Corby, Nicole, additional, Dunn, Matthew, additional, Johnson, Christopher, additional, Wood, Jonathan, additional, Clark, Susan, additional, Pelan, Sarah, additional, Griffiths, Guy, additional, Smith, Michelle, additional, Glithero, Rebecca, additional, Howden, Philip, additional, Barker, Nicholas, additional, Lloyd, Christine, additional, Stevens, Christopher, additional, Harley, Joanna, additional, Holt, Karen, additional, Panagiotidis, Georgios, additional, Lovell, Jamieson, additional, Beasley, Helen, additional, Henderson, Carl, additional, Gordon, Daria, additional, Auger, Katherine, additional, Wright, Deborah, additional, Collins, Joanna, additional, Raisen, Claire, additional, Dyer, Lauren, additional, Leung, Kenric, additional, Robertson, Lauren, additional, Ambridge, Kirsty, additional, Leongamornlert, Daniel, additional, McGuire, Sarah, additional, Gilderthorp, Ruth, additional, Griffiths, Coline, additional, Manthravadi, Deepa, additional, Nichol, Sarah, additional, Barker, Gary, additional, Whitehead, Siobhan, additional, Kay, Michael, additional, Brown, Jacqueline, additional, Murnane, Clare, additional, Gray, Emma, additional, Humphries, Matthew, additional, Sycamore, Neil, additional, Barker, Darren, additional, Saunders, David, additional, Wallis, Justene, additional, Babbage, Anne, additional, Hammond, Sian, additional, Mashreghi-Mohammadi, Maryam, additional, Barr, Lucy, additional, Martin, Sancha, additional, Wray, Paul, additional, Ellington, Andrew, additional, Matthews, Nicholas, additional, Ellwood, Matthew, additional, Woodmansey, Rebecca, additional, Clark, Graham, additional, Cooper, James D., additional, Tromans, Anthony, additional, Grafham, Darren, additional, Skuce, Carl, additional, Pandian, Richard, additional, Andrews, Robert, additional, Harrison, Elliot, additional, Kimberley, Andrew, additional, Garnett, Jane, additional, Fosker, Nigel, additional, Hall, Rebekah, additional, Garner, Patrick, additional, Kelly, Daniel, additional, Bird, Christine, additional, Palmer, Sophie, additional, Gehring, Ines, additional, Berger, Andrea, additional, Dooley, Christopher, additional, Ersan-Ürün, Zübeyde, additional, Eser, Cigdem, additional, Geiger, Horst, additional, Geisler, Maria, additional, Karotki, Lena, additional, Kirn, Anette, additional, Konantz, Judith, additional, Konantz, Martina, additional, Oberländer, Martina, additional, Rudolph-Geiger, Silke, additional, Teucke, Mathias, additional, Lanz, Christa, additional, Raddatz, Günter, additional, Osoegawa, Kazutoyo, additional, Zhu, Baoli, additional, Rapp, Amanda, additional, Widaa, Sara, additional, Langford, Cordelia, additional, Yang, Fengtang, additional, Schuster, Stephan C., additional, Carter, Nigel P., additional, Harrow, Jennifer, additional, Ning, Zemin, additional, Herrero, Javier, additional, Searle, Steve M. J., additional, Enright, Anton, additional, Geisler, Robert, additional, Plasterk, Ronald H. A., additional, Lee, Charles, additional, Westerfield, Monte, additional, de Jong, Pieter J., additional, Zon, Leonard I., additional, Postlethwait, John H., additional, Volhard, Christiane Nüsslein-, additional, Hubbard, Tim J. P., additional, Crollius, Hugues Roest, additional, Rogers, Jane, additional, and Stemple, Derek L., additional

Published
2013
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18. Correction: Mcph1-Deficient Mice Reveal a Role for MCPH1 in Otitis Media

Author

Chen, Jing, primary, Ingham, Neil, additional, Clare, Simon, additional, Raisen, Claire, additional, Vancollie, Valerie E., additional, Ismail, Ozama, additional, McIntyre, Rebecca E., additional, Tsang, Stephen H., additional, Mahajan, Vinit B., additional, Dougan, Gordon, additional, Adams, David J., additional, White, Jacqueline K., additional, and Steel, Karen P., additional

Published
2013
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19. Mcph1-Deficient Mice Reveal a Role for MCPH1 in Otitis Media

Author

Chen, Jing, primary, Ingham, Neil, additional, Clare, Simon, additional, Raisen, Claire, additional, Vancollie, Valerie E., additional, Ismail, Ozama, additional, McIntyre, Rebecca E., additional, Tsang, Stephen H., additional, Mahajan, Vinit B., additional, Dougan, Gordon, additional, Adams, David J., additional, White, Jacqueline K., additional, and Steel, Karen P., additional

Published
2013
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20. Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice

Author

Lawley, Trevor D., primary, Clare, Simon, additional, Walker, Alan W., additional, Stares, Mark D., additional, Connor, Thomas R., additional, Raisen, Claire, additional, Goulding, David, additional, Rad, Roland, additional, Schreiber, Fernanda, additional, Brandt, Cordelia, additional, Deakin, Laura J., additional, Pickard, Derek J., additional, Duncan, Sylvia H., additional, Flint, Harry J., additional, Clark, Taane G., additional, Parkhill, Julian, additional, and Dougan, Gordon, additional

Published
2012
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22. Antibiotic Treatment of Clostridium difficile Carrier Mice Triggers a Supershedder State, Spore-Mediated Transmission, and Severe Disease in Immunocompromised Hosts

Author

Lawley, Trevor D., primary, Clare, Simon, additional, Walker, Alan W., additional, Goulding, David, additional, Stabler, Richard A., additional, Croucher, Nicholas, additional, Mastroeni, Piero, additional, Scott, Paul, additional, Raisen, Claire, additional, Mottram, Lynda, additional, Fairweather, Neil F., additional, Wren, Brendan W., additional, Parkhill, Julian, additional, and Dougan, Gordon, additional

Published
2009
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23. Mcph1-Deficient Mice Reveal a Role for MCPH1 in Otitis Media.

Author

Chen, Jing, Ingham, Neil, Clare, Simon, Raisen, Claire, Vancollie, Valerie E., Ismail, Ozama, McIntyre, Rebecca E., Tsang, Stephen H., Mahajan, Vinit B., Dougan, Gordon, Adams, David J., White, Jacqueline K., and Steel, Karen P.

Subjects
OTITIS media, ELECTROPHYSIOLOGY, MUTAGENESIS, PHENOTYPES, ANIMAL genetics, BRAIN stem, EMBRYONIC stem cells, LABORATORY mice
Abstract

Otitis media is a common reason for hearing loss, especially in children. Otitis media is a multifactorial disease and environmental factors, anatomic dysmorphology and genetic predisposition can all contribute to its pathogenesis. However, the reasons for the variable susceptibility to otitis media are elusive. MCPH1 mutations cause primary microcephaly in humans. So far, no hearing impairment has been reported either in the MCPH1 patients or mouse models with Mcph1 deficiency. In this study, Mcph1-deficient (Mcph1tm1a/tm1a) mice were produced using embryonic stem cells with a targeted mutation by the Sanger Institute's Mouse Genetics Project. Auditory brainstem response measurements revealed that Mcph1tm1a/tm1a mice had mild to moderate hearing impairment with around 70% penetrance. We found otitis media with effusion in the hearing-impaired Mcph1tm1a/tm1a mice by anatomic and histological examinations. Expression of Mcph1 in the epithelial cells of middle ear cavities supported its involvement in the development of otitis media. Other defects of Mcph1tm1a/tm1a mice included small skull sizes, increased micronuclei in red blood cells, increased B cells and ocular abnormalities. These findings not only recapitulated the defects found in other Mcph1-deficient mice or MCPH1 patients, but also revealed an unexpected phenotype, otitis media with hearing impairment, which suggests Mcph1 is a new gene underlying genetic predisposition to otitis media. [ABSTRACT FROM AUTHOR]

Published
2013
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24. Antibiotic Treatment of Clostridium difficileCarrier Mice Triggers a Supershedder State, Spore-Mediated Transmission, and Severe Disease in Immunocompromised Hosts

Author

Lawley, Trevor D., Clare, Simon, Walker, Alan W., Goulding, David, Stabler, Richard A., Croucher, Nicholas, Mastroeni, Piero, Scott, Paul, Raisen, Claire, Mottram, Lynda, Fairweather, Neil F., Wren, Brendan W., Parkhill, Julian, and Dougan, Gordon

Abstract

ABSTRACTClostridium difficilepersists in hospitals by exploiting an infection cycle that is dependent on humans shedding highly resistant and infectious spores. Here we show that human virulent C. difficilecan asymptomatically colonize the intestines of immunocompetent mice, establishing a carrier state that persists for many months. C. difficilecarrier mice consistently shed low levels of spores but, surprisingly, do not transmit infection to cohabiting mice. However, antibiotic treatment of carriers triggers a highly contagious supershedder state, characterized by a dramatic reduction in the intestinal microbiota species diversity, C. difficileovergrowth, and excretion of high levels of spores. Stopping antibiotic treatment normally leads to recovery of the intestinal microbiota species diversity and suppresses C. difficilelevels, although some mice persist in the supershedding state for extended periods. Spore-mediated transmission to immunocompetent mice treated with antibiotics results in self-limiting mucosal inflammation of the large intestine. In contrast, transmission to mice whose innate immune responses are compromised (Myd88−/−) leads to a severe intestinal disease that is often fatal. Thus, mice can be used to investigate distinct stages of the C. difficileinfection cycle and can serve as a valuable surrogate for studying the spore-mediated transmission and interactions between C. difficileand the host and its microbiota, and the results obtained should guide infection control measures.

Published
2009
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25. The Role of Sphingosine-1-Phosphate Transporter Spns2 in Immune System Function.

Author

Nijnik, Anastasia, Clare, Simon, Hale, Christine, Jing Chen, Raisen, Claire, Mottram, Lynda, Lucas, Mark, Estabel, Jeanne, Ryder, Edward, Adissu, Hibret, Adams, Niels C., Ramirez-Solis, Ramiro, White, Jacqueline K., Steel, Karen P., Dougan, Gordon, and Hancock, Robert E. W.

Subjects
*SPHINGOSINE-1-phosphate, *IMMUNE system, *LIPIDS, *EMBRYOLOGY, *CELL membranes, *ATP-binding cassette transporters, *IMMUNOSUPPRESSIVE agents
Abstract

Sphingosine-l-phosphate (SIP) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of SIP transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate SIP transport in cell culture. Spns2 was also shown to control SIP activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different SIP-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2tmlalKOMP)Wtsi allele (Spns2tmla). The Spns2tmla/tmla animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2tmla/tmla mice closely mimicked the phenotypes of partial SIP deficiency and impaired SIP-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2tmla/tmla resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the SIP signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard. [ABSTRACT FROM AUTHOR]

Published
2012
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26. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

Andrew S. Waller, Igor Loncaric, Jaap A. Wagenaar, Luisa De Martino, Haythem Gharsa, Jos A. G. van Strijp, Emily J. Richardson, Nicholas Gleadall, Carmen Torres, Laurence Si Lok, Arjen J. Timmerman, Armando E. Hoet, Ewan M. Harrison, Tom P. Monie, Constança Pomba, Carla J. C. de Haas, Xiaoliang Ba, Anette Loeffler, Gerrit Koop, Mark A. Holmes, Edwin R. Chilvers, Gavin K. Paterson, Heleen M Klunder, Hermínia de Lencastre, Ruth N. Zadoks, Manouk Vrieling, Claire Raisen, Karin Bergström, J. Ross Fitzgerald, Kok P. M. van Kessel, Glenn F van Wigcheren, Daniel M. L. Storisteanu, Nazreen F. Hadjirin, Karim Ben Slama, Lok, Laurence [0000-0002-9364-4213], Monie, Tom [0000-0003-4097-1680], Ba, Xiaoliang [0000-0002-3882-3585], Chilvers, Edwin [0000-0002-4230-9677], Harrison, Ewan [0000-0003-2720-0507], Holmes, Mark [0000-0002-5454-1625], Apollo - University of Cambridge Repository, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M. L., Lok, Laurence S. C., Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nichola, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ro, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, DE MARTINO, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., De Haas, Carla, Van Kessel, Kok, Van Strijp, Jos A. G., Harrison, Ewan M., Holmes, Mark A., dFAH I&I, dFAH AVR, and dI&I I&I-4

Subjects
0301 basic medicine, Neutrophils, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Cell, HUMAN C5A RECEPTORS, Leukocidin, Host tropism, PROTEIN, Plasma protein binding, medicine.disease_cause, LYMPHOCYTES, Receptors, Interleukin-8B, Leukocidins, BINDING, Gene Order, CHEMOKINE RECEPTORS, GAMMA-HEMOLYSIN, Receptor, Phylogeny, Multidisciplinary, Bacteriologie, Bacteriology, Host Pathogen Interaction & Diagnostics, Staphylococcal Infections, Multidisciplinary Sciences, medicine.anatomical_structure, Staphylococcus aureus, Science & Technology - Other Topics, BOVINE, Pathogens, Protein Binding, Cell Survival, 030106 microbiology, Bacterial Toxins, Phage biology, Biology, Staphylococcal infections, LEUKOTOXIN, Article, Host Specificity, Microbiology, 03 medical and health sciences, PANTON-VALENTINE LEUCOCIDIN, Journal Article, medicine, Life Science, Animals, Humans, Horses, General, Prophage, Host Pathogen Interaction & Diagnostics, Science & Technology, Bacteriology, medicine.disease, Host Pathogen Interactie & Diagnostiek, 030104 developmental biology, Bacteriologie, Host Pathogen Interactie & Diagnostiek, Cattle, Horse Diseases
Abstract

Contains fulltext : 177770.pdf (Publisher’s version ) (Open Access) Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin; LukPQ. LukPQ is encoded on a 45 kb prophage (PhiSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component.

Published
2017
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