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4. Antigen Discovery for Next-Generation Pertussis Vaccines Using Immunoproteomics and Transposon-Directed Insertion Sequencing

Author

Gregg, Kelsey A, primary, Wang, Yihui, additional, Warfel, Jason, additional, Schoenfeld, Elizabeth, additional, Jankowska, Ewa, additional, Cipollo, John F, additional, Mayho, Matthew, additional, Boinett, Christine, additional, Prasad, Deepika, additional, Brickman, Timothy J, additional, Armstrong, Sandra K, additional, Parkhill, Julian, additional, Da Silva Antunes, Ricardo, additional, Sette, Alessandro, additional, Papin, James F, additional, Wolf, Roman, additional, and Merkel, Tod J, additional

Published
2022
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7. Antigen Discovery for Next-Generation Pertussis Vaccines Using Immunoproteomics and Transposon-Directed Insertion Sequencing.

Author

Gregg, Kelsey A, Wang, Yihui, Warfel, Jason, Schoenfeld, Elizabeth, Jankowska, Ewa, Cipollo, John F, Mayho, Matthew, Boinett, Christine, Prasad, Deepika, Brickman, Timothy J, Armstrong, Sandra K, Parkhill, Julian, Antunes, Ricardo Da Silva, Sette, Alessandro, Papin, James F, Wolf, Roman, and Merkel, Tod J

Subjects
WHOOPING cough vaccines, BORDETELLA pertussis, CONVALESCENT plasma, ANTIGENS, WHOOPING cough
Abstract

Background Despite high vaccination rates, the United States has experienced a resurgence in reported cases of pertussis after switching to the acellular pertussis vaccine, indicating a need for improved vaccines that enhance infection control. Methods Bordetella pertussis antigens recognized by convalescent-baboon serum and nasopharyngeal wash were identified by immunoproteomics and their subcellular localization predicted. Genes essential or important for persistence in the baboon airway were identified by transposon-directed insertion-site sequencing (TraDIS) analysis. Results In total, 314 B. pertussis antigens were identified by convalescent baboon serum and 748 by nasopharyngeal wash. Thirteen antigens were identified as immunogenic in baboons, essential for persistence in the airway by TraDIS, and membrane-localized: BP0840 (OmpP), Pal, OmpA2, BP1485, BamA, Pcp, MlaA, YfgL, BP2197, BP1569, MlaD, ComL, and BP0183. Conclusions The B. pertussis antigens identified as immunogenic, essential for persistence in the airway, and membrane-localized warrant further investigation for inclusion in vaccines designed to reduce or prevent carriage of bacteria in the airway of vaccinated individuals. [ABSTRACT FROM AUTHOR]

Published
2023
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8. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

Author

Rad, Roland, Rad, Lena, Wang, Wei, Strong, Alexander, Ponstingl, Hannes, Bronner, Iraad F, Mayho, Matthew, Steiger, Katja, Weber, Julia, Hieber, Maren, Veltkamp, Christian, Eser, Stefan, Geumann, Ulf, Öllinger, Rupert, Zukowska, Magdalena, Barenboim, Maxim, Maresch, Roman, Cadiñanos, Juan, Friedrich, Mathias, Varela, Ignacio, Constantino-Casas, Fernando, Sarver, Aaron, ten Hoeve, Jelle, Prosser, Haydn, Seidler, Barbara, Bauer, Judith, Heikenwälder, Mathias, Metzakopian, Emmanouil, Krug, Anne, Ehmer, Ursula, Schneider, Günter, Knösel, Thomas, Rümmele, Petra, Aust, Daniela, Grützmann, Robert, Pilarsky, Christian, Ning, Zemin, Wessels, Lodewyk, Schmid, Roland M, Quail, Michael A, Vassiliou, George, Esposito, Irene, Liu, Pentao, Saur, Dieter, and Bradley, Allan

Published
2015
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9. Functional analysis of colonization factor antigen I positive enterotoxigenic identifies genes implicated in survival in water and host colonization

Author

Abd El Ghany, Moataz, Barquist, Lars, Clare, Simon, Brandt, Cordelia, Mayho, Matthew, Joffre, Enrique, Sjöling, Åsa, Turner, A Keith, Klena, John D, Kingsley, Robert A, Hill-Cawthorne, Grant A, Dougan, Gordon, Pickard, Derek, and HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.

Subjects
CFA/I, H10407, fluids and secretions, ETEC, TraDIS, bacterial infections and mycoses, RNAseq, water survival and colonization, digestive system
Abstract

Enterotoxigenic Escherichia coli (ETEC) expressing the colonization pili CFA/I are common causes of diarrhoeal infections in humans. Here, we use a combination of transposon mutagenesis and transcriptomic analysis to identify genes and pathways that contribute to ETEC persistence in water environments and colonization of a mammalian host. ETEC persisting in water exhibit a distinct RNA expression profile from those growing in richer media. Multiple pathways were identified that contribute to water survival, including lipopolysaccharide biosynthesis and stress response regulons. The analysis also indicated that ETEC growing in vivo in mice encounter a bottleneck driving down the diversity of colonizing ETEC populations.

Published
2021

11. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author

Meng, Bo, primary, Kemp, Steven A., additional, Papa, Guido, additional, Datir, Rawlings, additional, Ferreira, Isabella A.T.M., additional, Marelli, Sara, additional, Harvey, William T., additional, Lytras, Spyros, additional, Mohamed, Ahmed, additional, Gallo, Giulia, additional, Thakur, Nazia, additional, Collier, Dami A., additional, Mlcochova, Petra, additional, Duncan, Lidia M., additional, Carabelli, Alessandro M., additional, Kenyon, Julia C., additional, Lever, Andrew M., additional, De Marco, Anna, additional, Saliba, Christian, additional, Culap, Katja, additional, Cameroni, Elisabetta, additional, Matheson, Nicholas J., additional, Piccoli, Luca, additional, Corti, Davide, additional, James, Leo C., additional, Robertson, David L., additional, Bailey, Dalan, additional, Gupta, Ravindra K., additional, Robson, Samuel C., additional, Loman, Nicholas J., additional, Connor, Thomas R., additional, Golubchik, Tanya, additional, Martinez Nunez, Rocio T., additional, Ludden, Catherine, additional, Corden, Sally, additional, Johnston, Ian, additional, Bonsall, David, additional, Smith, Colin P., additional, Awan, Ali R., additional, Bucca, Giselda, additional, Torok, M. Estee, additional, Saeed, Kordo, additional, Prieto, Jacqui A., additional, Jackson, David K., additional, Hamilton, William L., additional, Snell, Luke B., additional, Moore, Catherine, additional, Harrison, Ewan M., additional, Goncalves, Sonia, additional, Fairley, Derek J., additional, Loose, Matthew W., additional, Watkins, Joanne, additional, Livett, Rich, additional, Moses, Samuel, additional, Amato, Roberto, additional, Nicholls, Sam, additional, Bull, Matthew, additional, Smith, Darren L., additional, Barrett, Jeff, additional, Aanensen, David M., additional, Curran, Martin D., additional, Parmar, Surendra, additional, Aggarwal, Dinesh, additional, Shepherd, James G., additional, Parker, Matthew D., additional, Glaysher, Sharon, additional, Bashton, Matthew, additional, Underwood, Anthony P., additional, Pacchiarini, Nicole, additional, Loveson, Katie F., additional, Templeton, Kate E., additional, Langford, Cordelia F., additional, Sillitoe, John, additional, de Silva, Thushan I., additional, Wang, Dennis, additional, Kwiatkowski, Dominic, additional, Rambaut, Andrew, additional, O’Grady, Justin, additional, Cottrell, Simon, additional, Holden, Matthew T.G., additional, Thomson, Emma C., additional, Osman, Husam, additional, Andersson, Monique, additional, Chauhan, Anoop J., additional, Hassan-Ibrahim, Mohammed O., additional, Lawniczak, Mara, additional, Alderton, Alex, additional, Chand, Meera, additional, Constantinidou, Chrystala, additional, Unnikrishnan, Meera, additional, Darby, Alistair C., additional, Hiscox, Julian A., additional, Paterson, Steve, additional, Martincorena, Inigo, additional, Volz, Erik M., additional, Page, Andrew J., additional, Pybus, Oliver G., additional, Bassett, Andrew R., additional, Ariani, Cristina V., additional, Chapman, Michael H. Spencer, additional, Li, Kathy K., additional, Shah, Rajiv N., additional, Jesudason, Natasha G., additional, Taha, Yusri, additional, McHugh, Martin P., additional, Dewar, Rebecca, additional, Jahun, Aminu S., additional, McMurray, Claire, additional, Pandey, Sarojini, additional, McKenna, James P., additional, Nelson, Andrew, additional, Young, Gregory R., additional, McCann, Clare M., additional, Elliott, Scott, additional, Lowe, Hannah, additional, Temperton, Ben, additional, Roy, Sunando, additional, Price, Anna, additional, Rey, Sara, additional, Wyles, Matthew, additional, Rooke, Stefan, additional, Shaaban, Sharif, additional, de Cesare, Mariateresa, additional, Letchford, Laura, additional, Silveira, Siona, additional, Pelosi, Emanuela, additional, Wilson-Davies, Eleri, additional, Hosmillo, Myra, additional, O’Toole, Áine, additional, Hesketh, Andrew R., additional, Stark, Richard, additional, du Plessis, Louis, additional, Ruis, Chris, additional, Adams, Helen, additional, Bourgeois, Yann, additional, Michell, Stephen L., additional, Grammatopoulos, Dimitris, additional, Edgeworth, Jonathan, additional, Breuer, Judith, additional, Todd, John A., additional, Fraser, Christophe, additional, Buck, David, additional, John, Michaela, additional, Kay, Gemma L., additional, Palmer, Steve, additional, Peacock, Sharon J., additional, Heyburn, David, additional, Weldon, Danni, additional, Robinson, Esther, additional, McNally, Alan, additional, Muir, Peter, additional, Vipond, Ian B., additional, Boyes, John, additional, Sivaprakasam, Venkat, additional, Salluja, Tranprit, additional, Dervisevic, Samir, additional, Meader, Emma J., additional, Park, Naomi R., additional, Oliver, Karen, additional, Jeffries, Aaron R., additional, Ott, Sascha, additional, da Silva Filipe, Ana, additional, Simpson, David A., additional, Williams, Chris, additional, Masoli, Jane A.H., additional, Knight, Bridget A., additional, Jones, Christopher R., additional, Koshy, Cherian, additional, Ash, Amy, additional, Casey, Anna, additional, Bosworth, Andrew, additional, Ratcliffe, Liz, additional, Xu-McCrae, Li, additional, Pymont, Hannah M., additional, Hutchings, Stephanie, additional, Berry, Lisa, additional, Jones, Katie, additional, Halstead, Fenella, additional, Davis, Thomas, additional, Holmes, Christopher, additional, Iturriza-Gomara, Miren, additional, Lucaci, Anita O., additional, Randell, Paul Anthony, additional, Cox, Alison, additional, Madona, Pinglawathee, additional, Harris, Kathryn Ann, additional, Brown, Julianne Rose, additional, Mahungu, Tabitha W., additional, Irish-Tavares, Dianne, additional, Haque, Tanzina, additional, Hart, Jennifer, additional, Witele, Eric, additional, Fenton, Melisa Louise, additional, Liggett, Steven, additional, Graham, Clive, additional, Swindells, Emma, additional, Collins, Jennifer, additional, Eltringham, Gary, additional, Campbell, Sharon, additional, McClure, Patrick C., additional, Clark, Gemma, additional, Sloan, Tim J., additional, Jones, Carl, additional, Lynch, Jessica, additional, Warne, Ben, additional, Leonard, Steven, additional, Durham, Jillian, additional, Williams, Thomas, additional, Haldenby, Sam T., additional, Storey, Nathaniel, additional, Alikhan, Nabil-Fareed, additional, Holmes, Nadine, additional, Moore, Christopher, additional, Carlile, Matthew, additional, Perry, Malorie, additional, Craine, Noel, additional, Lyons, Ronan A., additional, Beckett, Angela H., additional, Goudarzi, Salman, additional, Fearn, Christopher, additional, Cook, Kate, additional, Dent, Hannah, additional, Paul, Hannah, additional, Davies, Robert, additional, Blane, Beth, additional, Girgis, Sophia T., additional, Beale, Mathew A., additional, Bellis, Katherine L., additional, Dorman, Matthew J., additional, Drury, Eleanor, additional, Kane, Leanne, additional, Kay, Sally, additional, McGuigan, Samantha, additional, Nelson, Rachel, additional, Prestwood, Liam, additional, Rajatileka, Shavanthi, additional, Batra, Rahul, additional, Williams, Rachel J., additional, Kristiansen, Mark, additional, Green, Angie, additional, Justice, Anita, additional, Mahanama, Adhyana I.K., additional, Samaraweera, Buddhini, additional, Hadjirin, Nazreen F., additional, Quick, Joshua, additional, Poplawski, Radoslaw, additional, Kermack, Leanne M., additional, Reynolds, Nicola, additional, Hall, Grant, additional, Chaudhry, Yasmin, additional, Pinckert, Malte L., additional, Georgana, Iliana, additional, Moll, Robin J., additional, Thornton, Alicia, additional, Myers, Richard, additional, Stockton, Joanne, additional, Williams, Charlotte A., additional, Yew, Wen C., additional, Trotter, Alexander J., additional, Trebes, Amy, additional, MacIntyre-Cockett, George, additional, Birchley, Alec, additional, Adams, Alexander, additional, Plimmer, Amy, additional, Gatica-Wilcox, Bree, additional, McKerr, Caoimhe, additional, Hilvers, Ember, additional, Jones, Hannah, additional, Asad, Hibo, additional, Coombes, Jason, additional, Evans, Johnathan M., additional, Fina, Laia, additional, Gilbert, Lauren, additional, Graham, Lee, additional, Cronin, Michelle, additional, Kumziene-Summerhayes, Sara, additional, Taylor, Sarah, additional, Jones, Sophie, additional, Groves, Danielle C., additional, Zhang, Peijun, additional, Gallis, Marta, additional, Louka, Stavroula F., additional, Starinskij, Igor, additional, Jackson, Chris, additional, Gourtovaia, Marina, additional, Tonkin-Hill, Gerry, additional, Lewis, Kevin, additional, Tovar-Corona, Jaime M., additional, James, Keith, additional, Baxter, Laura, additional, Alam, Mohammad T., additional, Orton, Richard J., additional, Hughes, Joseph, additional, Vattipally, Sreenu, additional, Ragonnet-Cronin, Manon, additional, Nascimento, Fabricia F., additional, Jorgensen, David, additional, Boyd, Olivia, additional, Geidelberg, Lily, additional, Zarebski, Alex E., additional, Raghwani, Jayna, additional, Kraemer, Moritz U.G., additional, Southgate, Joel, additional, Lindsey, Benjamin B., additional, Freeman, Timothy M., additional, Keatley, Jon-Paul, additional, Singer, Joshua B., additional, de Oliveira Martins, Leonardo, additional, Yeats, Corin A., additional, Abudahab, Khalil, additional, Taylor, Ben E.W., additional, Menegazzo, Mirko, additional, Danesh, John, additional, Hogsden, Wendy, additional, Eldirdiri, Sahar, additional, Kenyon, Anita, additional, Mason, Jenifer, additional, Robinson, Trevor I., additional, Holmes, Alison, additional, Price, James, additional, Hartley, John A., additional, Curran, Tanya, additional, Mather, Alison E., additional, Shankar, Giri, additional, Jones, Rachel, additional, Howe, Robin, additional, Morgan, Sian, additional, Wastenge, Elizabeth, additional, Chapman, Michael R., additional, Mookerjee, Siddharth, additional, Stanley, Rachael, additional, Smith, Wendy, additional, Peto, Timothy, additional, Eyre, David, additional, Crook, Derrick, additional, Vernet, Gabrielle, additional, Kitchen, Christine, additional, Gulliver, Huw, additional, Merrick, Ian, additional, Guest, Martyn, additional, Munn, Robert, additional, Bradley, Declan T., additional, Wyatt, Tim, additional, Beaver, Charlotte, additional, Foulser, Luke, additional, Palmer, Sophie, additional, Churcher, Carol M., additional, Brooks, Ellena, additional, Smith, Kim S., additional, Galai, Katerina, additional, McManus, Georgina M., additional, Bolt, Frances, additional, Coll, Francesc, additional, Meadows, Lizzie, additional, Attwood, Stephen W., additional, Davies, Alisha, additional, De Lacy, Elen, additional, Downing, Fatima, additional, Edwards, Sue, additional, Scarlett, Garry P., additional, Jeremiah, Sarah, additional, Smith, Nikki, additional, Leek, Danielle, additional, Sridhar, Sushmita, additional, Forrest, Sally, additional, Cormie, Claire, additional, Gill, Harmeet K., additional, Dias, Joana, additional, Higginson, Ellen E., additional, Maes, Mailis, additional, Young, Jamie, additional, Wantoch, Michelle, additional, Jamrozy, Dorota, additional, Lo, Stephanie, additional, Patel, Minal, additional, Hill, Verity, additional, Bewshea, Claire M., additional, Ellard, Sian, additional, Auckland, Cressida, additional, Harrison, Ian, additional, Bishop, Chloe, additional, Chalker, Vicki, additional, Richter, Alex, additional, Beggs, Andrew, additional, Best, Angus, additional, Percival, Benita, additional, Mirza, Jeremy, additional, Megram, Oliver, additional, Mayhew, Megan, additional, Crawford, Liam, additional, Ashcroft, Fiona, additional, Moles-Garcia, Emma, additional, Cumley, Nicola, additional, Hopes, Richard, additional, Asamaphan, Patawee, additional, Niebel, Marc O., additional, Gunson, Rory N., additional, Bradley, Amanda, additional, Maclean, Alasdair, additional, Mollett, Guy, additional, Blacow, Rachel, additional, Bird, Paul, additional, Helmer, Thomas, additional, Fallon, Karlie, additional, Tang, Julian, additional, Hale, Antony D., additional, Macfarlane-Smith, Louissa R., additional, Harper, Katherine L., additional, Carden, Holli, additional, Machin, Nicholas W., additional, Jackson, Kathryn A., additional, Ahmad, Shazaad S.Y., additional, George, Ryan P., additional, Turtle, Lance, additional, O’Toole, Elaine, additional, Watts, Joanne, additional, Breen, Cassie, additional, Cowell, Angela, additional, Alcolea-Medina, Adela, additional, Charalampous, Themoula, additional, Patel, Amita, additional, Levett, Lisa J., additional, Heaney, Judith, additional, Rowan, Aileen, additional, Taylor, Graham P., additional, Shah, Divya, additional, Atkinson, Laura, additional, Lee, Jack C.D., additional, Westhorpe, Adam P., additional, Jannoo, Riaz, additional, Lowe, Helen L., additional, Karamani, Angeliki, additional, Ensell, Leah, additional, Chatterton, Wendy, additional, Pusok, Monika, additional, Dadrah, Ashok, additional, Symmonds, Amanda, additional, Sluga, Graciela, additional, Molnar, Zoltan, additional, Baker, Paul, additional, Bonner, Stephen, additional, Essex, Sarah, additional, Barton, Edward, additional, Padgett, Debra, additional, Scott, Garren, additional, Greenaway, Jane, additional, Payne, Brendan A.I., additional, Burton-Fanning, Shirelle, additional, Waugh, Sheila, additional, Raviprakash, Veena, additional, Sheriff, Nicola, additional, Blakey, Victoria, additional, Williams, Lesley-Anne, additional, Moore, Jonathan, additional, Stonehouse, Susanne, additional, Smith, Louise, additional, Davidson, Rose K., additional, Bedford, Luke, additional, Coupland, Lindsay, additional, Wright, Victoria, additional, Chappell, Joseph G., additional, Tsoleridis, Theocharis, additional, Ball, Jonathan, additional, Khakh, Manjinder, additional, Fleming, Vicki M., additional, Lister, Michelle M., additional, Howson-Wells, Hannah C., additional, Berry, Louise, additional, Boswell, Tim, additional, Joseph, Amelia, additional, Willingham, Iona, additional, Duckworth, Nichola, additional, Walsh, Sarah, additional, Wise, Emma, additional, Moore, Nathan, additional, Mori, Matilde, additional, Cortes, Nick, additional, Kidd, Stephen, additional, Williams, Rebecca, additional, Gifford, Laura, additional, Bicknell, Kelly, additional, Wyllie, Sarah, additional, Lloyd, Allyson, additional, Impey, Robert, additional, Malone, Cassandra S., additional, Cogger, Benjamin J., additional, Levene, Nick, additional, Monaghan, Lynn, additional, Keeley, Alexander J., additional, Partridge, David G., additional, Raza, Mohammad, additional, Evans, Cariad, additional, Johnson, Kate, additional, Betteridge, Emma, additional, Farr, Ben W., additional, Goodwin, Scott, additional, Quail, Michael A., additional, Scott, Carol, additional, Shirley, Lesley, additional, Thurston, Scott A.J., additional, Rajan, Diana, additional, Bronner, Iraad F., additional, Aigrain, Louise, additional, Redshaw, Nicholas M., additional, Lensing, Stefanie V., additional, McCarthy, Shane, additional, Makunin, Alex, additional, Balcazar, Carlos E., additional, Gallagher, Michael D., additional, Williamson, Kathleen A., additional, Stanton, Thomas D., additional, Michelsen, Michelle L., additional, Warwick-Dugdale, Joanna, additional, Manley, Robin, additional, Farbos, Audrey, additional, Harrison, James W., additional, Sambles, Christine M., additional, Studholme, David J., additional, Lackenby, Angie, additional, Mbisa, Tamyo, additional, Platt, Steven, additional, Miah, Shahjahan, additional, Bibby, David, additional, Manso, Carmen, additional, Hubb, Jonathan, additional, Dabrera, Gavin, additional, Ramsay, Mary, additional, Bradshaw, Daniel, additional, Schaefer, Ulf, additional, Groves, Natalie, additional, Gallagher, Eileen, additional, Lee, David, additional, Williams, David, additional, Ellaby, Nicholas, additional, Hartman, Hassan, additional, Manesis, Nikos, additional, Patel, Vineet, additional, Ledesma, Juan, additional, Twohig, Katherine A., additional, Allara, Elias, additional, Pearson, Clare, additional, Cheng, Jeffrey K.J., additional, Bridgewater, Hannah E., additional, Frost, Lucy R., additional, Taylor-Joyce, Grace, additional, Brown, Paul E., additional, Tong, Lily, additional, Broos, Alice, additional, Mair, Daniel, additional, Nichols, Jenna, additional, Carmichael, Stephen N., additional, Smollett, Katherine L., additional, Nomikou, Kyriaki, additional, Aranday-Cortes, Elihu, additional, Johnson, Natasha, additional, Nickbakhsh, Seema, additional, Vamos, Edith E., additional, Hughes, Margaret, additional, Rainbow, Lucille, additional, Eccles, Richard, additional, Nelson, Charlotte, additional, Whitehead, Mark, additional, Gregory, Richard, additional, Gemmell, Matthew, additional, Wierzbicki, Claudia, additional, Webster, Hermione J., additional, Fisher, Chloe L., additional, Signell, Adrian W., additional, Betancor, Gilberto, additional, Wilson, Harry D., additional, Nebbia, Gaia, additional, Flaviani, Flavia, additional, Cerda, Alberto C., additional, Merrill, Tammy V., additional, Wilson, Rebekah E., additional, Cotic, Marius, additional, Bayzid, Nadua, additional, Thompson, Thomas, additional, Acheson, Erwan, additional, Rushton, Steven, additional, O’Brien, Sarah, additional, Baker, David J., additional, Rudder, Steven, additional, Aydin, Alp, additional, Sang, Fei, additional, Debebe, Johnny, additional, Francois, Sarah, additional, Vasylyeva, Tetyana I., additional, Zamudio, Marina Escalera, additional, Gutierrez, Bernardo, additional, Marchbank, Angela, additional, Maksimovic, Joshua, additional, Spellman, Karla, additional, McCluggage, Kathryn, additional, Morgan, Mari, additional, Beer, Robert, additional, Afifi, Safiah, additional, Workman, Trudy, additional, Fuller, William, additional, Bresner, Catherine, additional, Angyal, Adrienn, additional, Green, Luke R., additional, Parsons, Paul J., additional, Tucker, Rachel M., additional, Brown, Rebecca, additional, Whiteley, Max, additional, Bonfield, James, additional, Puethe, Christoph, additional, Whitwham, Andrew, additional, Liddle, Jennifier, additional, Rowe, Will, additional, Siveroni, Igor, additional, Le-Viet, Thanh, additional, Gaskin, Amy, additional, Johnson, Rob, additional, Abnizova, Irina, additional, Ali, Mozam, additional, Allen, Laura, additional, Anderson, Ralph, additional, Ariani, Cristina, additional, Austin-Guest, Siobhan, additional, Bala, Sendu, additional, Barrett, Jeffrey, additional, Bassett, Andrew, additional, Battleday, Kristina, additional, Beal, James, additional, Beale, Mathew, additional, Bellany, Sam, additional, Bellerby, Tristram, additional, Bellis, Katie, additional, Berger, Duncan, additional, Berriman, Matt, additional, Bevan, Paul, additional, Binley, Simon, additional, Bishop, Jason, additional, Blackburn, Kirsty, additional, Boughton, Nick, additional, Bowker, Sam, additional, Brendler-Spaeth, Timothy, additional, Bronner, Iraad, additional, Brooklyn, Tanya, additional, Buddenborg, Sarah Kay, additional, Bush, Robert, additional, Caetano, Catarina, additional, Cagan, Alex, additional, Carter, Nicola, additional, Cartwright, Joanna, additional, Monteiro, Tiago Carvalho, additional, Chapman, Liz, additional, Chillingworth, Tracey-Jane, additional, Clapham, Peter, additional, Clark, Richard, additional, Clarke, Adrian, additional, Clarke, Catriona, additional, Cole, Daryl, additional, Cook, Elizabeth, additional, Coppola, Maria, additional, Cornell, Linda, additional, Cornwell, Clare, additional, Corton, Craig, additional, Crackett, Abby, additional, Cranage, Alison, additional, Craven, Harriet, additional, Craw, Sarah, additional, Crawford, Mark, additional, Cutts, Tim, additional, Dabrowska, Monika, additional, Davies, Matt, additional, Dawson, Joseph, additional, Day, Callum, additional, Densem, Aiden, additional, Dibling, Thomas, additional, Dockree, Cat, additional, Dodd, David, additional, Dogga, Sunil, additional, Dorman, Matthew, additional, Dougan, Gordon, additional, Dougherty, Martin, additional, Dove, Alexander, additional, Drummond, Lucy, additional, Dudek, Monika, additional, Durrant, Laura, additional, Easthope, Elizabeth, additional, Eckert, Sabine, additional, Ellis, Pete, additional, Farr, Ben, additional, Fenton, Michael, additional, Ferrero, Marcella, additional, Flack, Neil, additional, Fordham, Howerd, additional, Forsythe, Grace, additional, Francis, Matt, additional, Fraser, Audrey, additional, Freeman, Adam, additional, Galvin, Anastasia, additional, Garcia-Casado, Maria, additional, Gedny, Alex, additional, Girgis, Sophia, additional, Glover, James, additional, Gould, Oliver, additional, Gray, Andy, additional, Gray, Emma, additional, Griffiths, Coline, additional, Gu, Yong, additional, Guerin, Florence, additional, Hamilton, Will, additional, Hanks, Hannah, additional, Harrison, Ewan, additional, Harrott, Alexandria, additional, Harry, Edward, additional, Harvison, Julia, additional, Heath, Paul, additional, Hernandez-Koutoucheva, Anastasia, additional, Hobbs, Rhiannon, additional, Holland, Dave, additional, Holmes, Sarah, additional, Hornett, Gary, additional, Hough, Nicholas, additional, Huckle, Liz, additional, Hughes-Hallet, Lena, additional, Hunter, Adam, additional, Inglis, Stephen, additional, Iqbal, Sameena, additional, Jackson, Adam, additional, Jackson, David, additional, Verdejo, Carlos Jimenez, additional, Jones, Matthew, additional, Kallepally, Kalyan, additional, Kay, Keely, additional, Keatley, Jon, additional, Keith, Alan, additional, King, Alison, additional, Kitchin, Lucy, additional, Kleanthous, Matt, additional, Klimekova, Martina, additional, Korlevic, Petra, additional, Krasheninnkova, Ksenia, additional, Lane, Greg, additional, Langford, Cordelia, additional, Laverack, Adam, additional, Law, Katharine, additional, Lensing, Stefanie, additional, Lewis-Wade, Amanah, additional, Liddle, Jennifer, additional, Lin, Quan, additional, Lindsay, Sarah, additional, Linsdell, Sally, additional, Long, Rhona, additional, Lovell, Jamie, additional, Lovell, Jon, additional, Mack, James, additional, Maddison, Mark, additional, Makunin, Aleksei, additional, Mamun, Irfan, additional, Mansfield, Jenny, additional, Marriott, Neil, additional, Martin, Matt, additional, Mayho, Matthew, additional, McClintock, Jo, additional, McHugh, Sandra, additional, MapcMinn, Liz, additional, Meadows, Carl, additional, Mobley, Emily, additional, Moll, Robin, additional, Morra, Maria, additional, Morrow, Leanne, additional, Murie, Kathryn, additional, Nash, Sian, additional, Nathwani, Claire, additional, Naydenova, Plamena, additional, Neaverson, Alexandra, additional, Nerou, Ed, additional, Nicholson, Jon, additional, Nimz, Tabea, additional, Noell, Guillaume G., additional, O’Meara, Sarah, additional, Ohan, Valeriu, additional, Olney, Charles, additional, Ormond, Doug, additional, Oszlanczi, Agnes, additional, Pang, Yoke Fei, additional, Pardubska, Barbora, additional, Park, Naomi, additional, Parmar, Aaron, additional, Patel, Gaurang, additional, Payne, Maggie, additional, Peacock, Sharon, additional, Petersen, Arabella, additional, Plowman, Deborah, additional, Preston, Tom, additional, Quail, Michael, additional, Rance, Richard, additional, Rawlings, Suzannah, additional, Redshaw, Nicholas, additional, Reynolds, Joe, additional, Reynolds, Mark, additional, Rice, Simon, additional, Richardson, Matt, additional, Roberts, Connor, additional, Robinson, Katrina, additional, Robinson, Melanie, additional, Robinson, David, additional, Rogers, Hazel, additional, Rojo, Eduardo Martin, additional, Roopra, Daljit, additional, Rose, Mark, additional, Rudd, Luke, additional, Sadri, Ramin, additional, Salmon, Nicholas, additional, Saul, David, additional, Schwach, Frank, additional, Seekings, Phil, additional, Simms, Alison, additional, Sinnott, Matt, additional, Sivadasan, Shanthi, additional, Siwek, Bart, additional, Sizer, Dale, additional, Skeldon, Kenneth, additional, Skelton, Jason, additional, Slater-Tunstill, Joanna, additional, Sloper, Lisa, additional, Smerdon, Nathalie, additional, Smith, Chris, additional, Smith, Christen, additional, Smith, James, additional, Smith, Katie, additional, Smith, Michelle, additional, Smith, Sean, additional, Smith, Tina, additional, Sneade, Leighton, additional, Soria, Carmen Diaz, additional, Sousa, Catarina, additional, Souster, Emily, additional, Sparkes, Andrew, additional, Spencer-Chapman, Michael, additional, Squares, Janet, additional, Stanley, Robert, additional, Steed, Claire, additional, Stickland, Tim, additional, Still, Ian, additional, Stratton, Mike, additional, Strickland, Michelle, additional, Swann, Allen, additional, Swiatkowska, Agnieszka, additional, Sycamore, Neil, additional, Swift, Emma, additional, Symons, Edward, additional, Szluha, Suzanne, additional, Taluy, Emma, additional, Tao, Nunu, additional, Taylor, Katy, additional, Taylor, Sam, additional, Thompson, Stacey, additional, Thompson, Mark, additional, Thomson, Mark, additional, Thomson, Nicholas, additional, Thurston, Scott, additional, Toombs, Dee, additional, Topping, Benjamin, additional, Tovar-Corona, Jaime, additional, Ungureanu, Daniel, additional, Uphill, James, additional, Urbanova, Jana, additional, Van, Philip Jansen, additional, Vancollie, Valerie, additional, Voak, Paul, additional, Walker, Danielle, additional, Walker, Matthew, additional, Waller, Matt, additional, Ward, Gary, additional, Weatherhogg, Charlie, additional, Webb, Niki, additional, Wells, Alan, additional, Wells, Eloise, additional, Westwood, Luke, additional, Whipp, Theo, additional, Whiteley, Thomas, additional, Whitton, Georgia, additional, Widaa, Sara, additional, Williams, Mia, additional, Wilson, Mark, additional, and Wright, Sean, additional

Published
2021
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12. A Minimally Morphologically Destructive Approach for DNA Retrieval and Whole-Genome Shotgun Sequencing of Pinned Historic Dipteran Vector Species

Author

Korlević, Petra, McAlister, Erica, Mayho, Matthew, Makunin, Alex, Flicek, Paul, Lawniczak, Mara KN, Korlević, Petra, McAlister, Erica, Mayho, Matthew, Makunin, Alex, Flicek, Paul, and Lawniczak, Mara KN

Abstract

Museum collections contain enormous quantities of insect specimens collected over the past century, covering a period of increased and varied insecticide usage. These historic collections are therefore incredibly valuable as genomic snapshots of organisms before, during, and after exposure to novel selective pressures. However, these samples come with their own challenges compared with present-day collections, as they are fragile and retrievable DNA is low yield and fragmented. In this article, we tested several DNA extraction procedures across pinned historic Diptera specimens from four disease vector genera: Anopheles, Aedes, Culex, and Glossina. We identify an approach that minimizes morphological damage while maximizing DNA retrieval for Illumina library preparation and sequencing that can accommodate the fragmented and low yield nature of historic DNA. We identify several key points in retrieving sufficient DNA while keeping morphological damage to a minimum: an initial rehydration step, a short incubation without agitation in a modified low salt Proteinase K buffer (referred to as “lysis buffer C” throughout), and critical point drying of samples post-extraction to prevent tissue collapse caused by air drying. The suggested method presented here provides a solid foundation for exploring the genomes and morphology of historic Diptera collections.

Published
2021

13. Functional analysis of colonization factor antigen I positive enterotoxigenic Escherichia coli identifies genes implicated in survival in water and host colonization

Author

Abd El Ghany, Moataz, primary, Barquist, Lars, additional, Clare, Simon, additional, Brandt, Cordelia, additional, Mayho, Matthew, additional, Joffre´, Enrique, additional, Sjöling, Åsa, additional, Turner, A. Keith, additional, Klena, John D., additional, Kingsley, Robert A., additional, Hill-Cawthorne, Grant A., additional, Dougan, Gordon, additional, and Pickard, Derek, additional

Published
2021
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14. The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

Author

Zhang, Min, primary, Wang, Chengqi, additional, Oberstaller, Jenna, additional, Thomas, Phaedra, additional, Otto, Thomas D., additional, Casandra, Debora, additional, Boyapalle, Sandhya, additional, Adapa, Swamy R., additional, Xu, Shulin, additional, Button-Simons, Katrina, additional, Mayho, Matthew, additional, Rayner, Julian C., additional, Ferdig, Michael T., additional, Jiang, Rays H. Y., additional, and Adams, John H., additional

Published
2020
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17. Minimally Morphologically Destructive Approach for DNA Retrieval and Whole-Genome Shotgun Sequencing of Pinned Historic Dipteran Vector Species.

Author

Korlević, Petra, McAlister, Erica, Mayho, Matthew, Makunin, Alex, Flicek, Paul, and Lawniczak, Mara K N

Subjects
SHOTGUN sequencing, DIPTERA, DNA, INSECT collection & preservation, DISEASE vectors
Abstract

Museum collections contain enormous quantities of insect specimens collected over the past century, covering a period of increased and varied insecticide usage. These historic collections are therefore incredibly valuable as genomic snapshots of organisms before, during, and after exposure to novel selective pressures. However, these samples come with their own challenges compared with present-day collections, as they are fragile and retrievable DNA is low yield and fragmented. In this article, we tested several DNA extraction procedures across pinned historic Diptera specimens from four disease vector genera: Anopheles , Aedes , Culex , and Glossina. We identify an approach that minimizes morphological damage while maximizing DNA retrieval for Illumina library preparation and sequencing that can accommodate the fragmented and low yield nature of historic DNA. We identify several key points in retrieving sufficient DNA while keeping morphological damage to a minimum: an initial rehydration step, a short incubation without agitation in a modified low salt Proteinase K buffer (referred to as "lysis buffer C" throughout), and critical point drying of samples post-extraction to prevent tissue collapse caused by air drying. The suggested method presented here provides a solid foundation for exploring the genomes and morphology of historic Diptera collections. [ABSTRACT FROM AUTHOR]

Published
2021
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18. Genome-wide Analysis of Salmonella enterica serovar Typhi in Humanized Mice Reveals Key Virulence Features

Author

Karlinsey, Joyce E., primary, Stepien, Taylor A., additional, Mayho, Matthew, additional, Singletary, Larissa A., additional, Bingham-Ramos, Lacey K., additional, Brehm, Michael A., additional, Greiner, Dale L., additional, Shultz, Leonard D., additional, Gallagher, Larry A., additional, Bawn, Matt, additional, Kingsley, Robert A., additional, Libby, Stephen J., additional, and Fang, Ferric C., additional

Published
2019
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19. Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii

Author

Boinett, Christine J., primary, Cain, Amy K., additional, Hawkey, Jane, additional, Do Hoang, Nhu Tran, additional, Khanh, Nhu Nguyen Thi, additional, Thanh, Duy Pham, additional, Dordel, Janina, additional, Campbell, James I., additional, Lan, Nguyen Phu Huong, additional, Mayho, Matthew, additional, Langridge, Gemma C., additional, Hadfield, James, additional, Chau, Nguyen Van Vinh, additional, Thwaites, Guy E., additional, Parkhill, Julian, additional, Thomson, Nicholas R., additional, Holt, Kathryn E., additional, and Baker, Stephen, additional

Published
2019
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21. A global genomic approach uncovers novel components for twitching motility-mediated biofilm expansion in Pseudomonas aeruginosa

Author

Nolan, Laura M., primary, Whitchurch, Cynthia B., additional, Barquist, Lars, additional, Katrib, Marilyn, additional, Boinett, Christine J., additional, Mayho, Matthew, additional, Goulding, David, additional, Charles, Ian G., additional, Filloux, Alain, additional, Parkhill, Julian, additional, and Cain, Amy K., additional

Published
2018
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22. Comparative genomics of the emerging human pathogen Photorhabdus asymbiotica with the insect pathogen Photorhabdus luminescens

Author

Churcher Carol, Simmonds Mark, Smith Frances, Bason Nathalie, Mayho Matthew, Ormond Douglas, Clark Louise, Bignell Alexandra, Barron Andrew, Vlisidou Isabella, Sanchez-Contreras Maria, Corton Craig, Crossman Lisa, Waterfield Nicholas R, Wilkinson Paul, Harris David, Thompson Nicholas R, Quail Michael, Parkhill Julian, and ffrench-Constant Richard H

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The Gram-negative bacterium Photorhabdus asymbiotica (Pa) has been recovered from human infections in both North America and Australia. Recently, Pa has been shown to have a nematode vector that can also infect insects, like its sister species the insect pathogen P. luminescens (Pl). To understand the relationship between pathogenicity to insects and humans in Photorhabdus we have sequenced the complete genome of Pa strain ATCC43949 from North America. This strain (formerly referred to as Xenorhabdus luminescens strain 2) was isolated in 1977 from the blood of an 80 year old female patient with endocarditis, in Maryland, USA. Here we compare the complete genome of Pa ATCC43949 with that of the previously sequenced insect pathogen P. luminescens strain TT01 which was isolated from its entomopathogenic nematode vector collected from soil in Trinidad and Tobago. Results We found that the human pathogen Pa had a smaller genome (5,064,808 bp) than that of the insect pathogen Pl (5,688,987 bp) but that each pathogen carries approximately one megabase of DNA that is unique to each strain. The reduced size of the Pa genome is associated with a smaller diversity in insecticidal genes such as those encoding the Toxin complexes (Tc's), Makes caterpillars floppy (Mcf) toxins and the Photorhabdus Virulence Cassettes (PVCs). The Pa genome, however, also shows the addition of a plasmid related to pMT1 from Yersinia pestis and several novel pathogenicity islands including a novel Type Three Secretion System (TTSS) encoding island. Together these data suggest that Pa may show virulence against man via the acquisition of the pMT1-like plasmid and specific effectors, such as SopB, that promote its persistence inside human macrophages. Interestingly the loss of insecticidal genes in Pa is not reflected by a loss of pathogenicity towards insects. Conclusion Our results suggest that North American isolates of Pa have acquired virulence against man via the acquisition of a plasmid and specific virulence factors with similarity to those shown to play roles in pathogenicity against humans in other bacteria.

Published
2009
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26. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

Author

Rad, Roland, primary, Rad, Lena, additional, Wang, Wei, additional, Strong, Alexander, additional, Ponstingl, Hannes, additional, Bronner, Iraad F, additional, Mayho, Matthew, additional, Steiger, Katja, additional, Weber, Julia, additional, Hieber, Maren, additional, Veltkamp, Christian, additional, Eser, Stefan, additional, Geumann, Ulf, additional, Öllinger, Rupert, additional, Zukowska, Magdalena, additional, Barenboim, Maxim, additional, Maresch, Roman, additional, Cadiñanos, Juan, additional, Friedrich, Mathias, additional, Varela, Ignacio, additional, Constantino-Casas, Fernando, additional, Sarver, Aaron, additional, ten Hoeve, Jelle, additional, Prosser, Haydn, additional, Seidler, Barbara, additional, Bauer, Judith, additional, Heikenwälder, Mathias, additional, Metzakopian, Emmanouil, additional, Krug, Anne, additional, Ehmer, Ursula, additional, Schneider, Günter, additional, Knösel, Thomas, additional, Rümmele, Petra, additional, Aust, Daniela, additional, Grützmann, Robert, additional, Pilarsky, Christian, additional, Ning, Zemin, additional, Wessels, Lodewyk, additional, Schmid, Roland M, additional, Quail, Michael A, additional, Vassiliou, George, additional, Esposito, Irene, additional, Liu, Pentao, additional, Saur, Dieter, additional, and Bradley, Allan, additional

Published
2014
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28. Comparative genomics of the emerging human pathogen Photorhabdus asymbiotica with the insect pathogen Photorhabdus luminescens

Author

Wilkinson, Paul, primary, Waterfield, Nicholas R, additional, Crossman, Lisa, additional, Corton, Craig, additional, Sanchez-Contreras, Maria, additional, Vlisidou, Isabella, additional, Barron, Andrew, additional, Bignell, Alexandra, additional, Clark, Louise, additional, Ormond, Douglas, additional, Mayho, Matthew, additional, Bason, Nathalie, additional, Smith, Frances, additional, Simmonds, Mark, additional, Churcher, Carol, additional, Harris, David, additional, Thompson, Nicholas R, additional, Quail, Michael, additional, Parkhill, Julian, additional, and ffrench-Constant, Richard H, additional

Published
2009
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29. Genes Required for the Fitness of Salmonella entericaSerovar Typhimurium during Infection of Immunodeficient gp91−/−phoxMice

Author

Grant, Andrew J., Oshota, Olusegun, Chaudhuri, Roy R., Mayho, Matthew, Peters, Sarah E., Clare, Simon, Maskell, Duncan J., and Mastroeni, Pietro

Abstract

ABSTRACTSalmonella entericacauses systemic diseases (typhoid and paratyphoid fever), nontyphoidal septicemia (NTS), and gastroenteritis in humans and other animals worldwide. An important but underrecognized emerging infectious disease problem in sub-Saharan Africa is NTS in children and immunocompromised adults. A current goal is to identify Salmonellamutants that are not pathogenic in the absence of key components of the immune system such as might be found in immunocompromised hosts. Such attenuated strains have the potential to be used as live vaccines. We have used transposon-directed insertion site sequencing (TraDIS) to screen mutants of Salmonella entericaserovar Typhimurium for their ability to infect and grow in the tissues of wild-type and immunodeficient mice. This was to identify bacterial genes that might be deleted for the development of live attenuated vaccines that would be safer to use in situations and/or geographical areas where immunodeficiencies are prevalent. The relative fitness of each of 9,356 transposon mutants, representing mutations in 3,139 different genes, was determined in gp91−/−phoxmice. Mutations in certain genes led to reduced fitness in both wild-type and mutant mice. To validate these results, these genes were mutated by allelic replacement, and resultant mutants were retested for fitness in the mice. A defined deletion mutant of cysEwas attenuated in C57BL/6 wild-type mice and immunodeficient gp91−/−phoxmice and was effective as a live vaccine in wild-type mice.

Published
2016
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30. Comparative genomics of the emerging human pathogenPhotorhabdus asymbiotica with the insect pathogen Photorhabdusluminescens.

Author

Wilkinson, Paul, Waterfield, Nicholas R., Crossman, Lisa, Corton, Craig, Sanchez-Contreras, Maria, Vlisidou, Isabella, Barron, Andrew, Bignell, Alexandra, Clark, Louise, Ormond, Douglas, Mayho, Matthew, Bason, Nathalie, Smith, Frances, Simmonds, Mark, Churcher, Carol, Harris, David, Thompson, Nicholas R., Quail, Michael, Parkhill, Julian, and ffrench-Constant, Richard H.

Subjects
GRAM-negative bacteria, NEMATODES as carriers of disease, PLANT nematodes as carriers of disease
Abstract

Background: The Gram-negative bacterium Photorhabdus asymbiotica (Pa) has been recovered from human infections in both North America and Australia. Recently, Pa has been shown to have a nematode vector that can also infect insects, like its sister species the insect pathogen P. luminescens (Pl). To understand the relationship between pathogenicity to insects and humans in Photorhabdus we have sequenced the complete genome of Pa strain ATCC43949 from North America. This strain (formerly referred to as Xenorhabdus luminescens strain 2) was isolated in 1977 from the blood of an 80 year old female patient with endocarditis, in Maryland, USA. Here we compare the complete genome of Pa ATCC43949 with that of the previously sequenced insect pathogen P. luminescens strain TT01 which was isolated from its entomopathogenic nematode vector collected from soil in Trinidad and Tobago. Results: We found that the human pathogen Pa had a smaller genome (5,064,808 bp) than that of the insect pathogen Pl (5,688,987 bp) but that each pathogen carries approximately one megabase of DNA that is unique to each strain. The reduced size of the Pa genome is associated with a smaller diversity in insecticidal genes such as those encoding the Toxin complexes (Tc's), Makes caterpillars floppy (Mcf) toxins and the Photorhabdus Virulence Cassettes (PVCs). The Pa genome, however, also shows the addition of a plasmid related to pMT1 from Yersinia pestis and several novel pathogenicity islands including a novel Type Three Secretion System (TTSS) encoding island. Together these data suggest that Pa may show virulence against man via the acquisition of the pMT1-like plasmid and specific effectors, such as SopB, that promote its persistence inside human macrophages. Interestingly the loss of insecticidal genes in Pa is not reflected by a loss of pathogenicity towards insects. Conclusion: Our results suggest that North American isolates of Pa have acquired virulence against man via the acquisition of a plasmid and specific virulence factors with similarity to those shown to play roles in pathogenicity against humans in other bacteria. [ABSTRACT FROM AUTHOR]

Published
2009
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31. Morphological, genomic and transcriptomic responses of Klebsiella pneumoniae to the last-line antibiotic colistin

Author

Cain, Amy K, Boinett, Christine J, Barquist, Lars, Dordel, Janina, Fookes, Maria, Mayho, Matthew, Ellington, Matthew J, Goulding, David, Pickard, Derek, Wick, Ryan R, Holt, Kathryn E, Parkhill, Julian, and Thomson, Nicholas R

Subjects
Klebsiella pneumoniae, Phenotype, Genotype, Colistin, Genes, Bacterial, Drug Resistance, Bacterial, Mutation, Genomics, Transcriptome, Phylogeny, 3. Good health, Anti-Bacterial Agents
Abstract

Colistin remains one of the few antibiotics effective against multi-drug resistant (MDR) hospital pathogens, such as Klebsiella pneumoniae. Yet resistance to this last-line drug is rapidly increasing. Characterized mechanisms of colR in K. pneumoniae are largely due to chromosomal mutations in two-component regulators, although a plasmid-mediated colR mechanism has recently been uncovered. However, the effects of intrinsic colistin resistance are yet to be characterized on a whole-genome level. Here, we used a genomics-based approach to understand the mechanisms of adaptive colR acquisition in K. pneumoniae. In controlled directed-evolution experiments we observed two distinct paths to colistin resistance acquisition. Whole genome sequencing identified mutations in two colistin resistance genes: in the known colR regulator phoQ which became fixed in the population and resulted in a single amino acid change, and unstable minority variants in the recently described two-component sensor crrB. Through RNAseq and microscopy, we reveal the broad range of effects that colistin exposure has on the cell. This study is the first to use genomics to identify a population of minority variants with mutations in a colR gene in K. pneumoniae., This work was supported by the Wellcome Trust grant number WT098051. The salaries of AKC and CJB were supported by the Medical Research Council [grant number G1100100/1] and MJE is supported by Public Health England. LB is supported by a research fellowship from the Alexander von Humboldt Stiftung/Foundation. KEH is supported by the NHMRC of Australia (Fellowship #1061409).

32. Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii

Author

Boinett, Christine J, Cain, Amy K, Hawkey, Jane, Do Hoang, Nhu Tran, Khanh, Nhu Nguyen Thi, Thanh, Duy Pham, Dordel, Janina, Campbell, James I, Lan, Nguyen Phu Huong, Mayho, Matthew, Langridge, Gemma C, Hadfield, James, Chau, Nguyen Van Vinh, Thwaites, Guy E, Parkhill, Julian, Thomson, Nicholas R, Holt, Kathryn E, and Baker, Stephen

Subjects
Acinetobacter baumannii, Colistin, High-Throughput Nucleotide Sequencing, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, RNAseq, 3. Good health, Anti-Bacterial Agents, Lipid A, colistin resistance, Bacterial Proteins, Vietnam, whole-genome sequencing, TraDIS, Drug Resistance, Bacterial, Mutation, polycyclic compounds, multi-drug resistance, bacteria, lipids (amino acids, peptides, and proteins), Phospholipids, Acinetobacter Infections
Abstract

The increasing incidence and emergence of multi-drug resistant (MDR) Acinetobacter baumannii has become a major global health concern. Colistin is a historic antimicrobial that has become commonly used as a treatment for MDR A. baumannii infections. The increase in colistin usage has been mirrored by an increase in colistin resistance. We aimed to identify the mechanisms associated with colistin resistance in A. baumannii using multiple high-throughput-sequencing technologies, including transposon-directed insertion site sequencing (TraDIS), RNA sequencing (RNAseq) and whole-genome sequencing (WGS) to investigate the genotypic changes of colistin resistance in A. baumannii. Using TraDIS, we found that genes involved in drug efflux (adeIJK), and phospholipid (mlaC, mlaF and mlaD) and lipooligosaccharide synthesis (lpxC and lpsO) were required for survival in sub-inhibitory concentrations of colistin. Transcriptomic (RNAseq) analysis revealed that expression of genes encoding efflux proteins (adeI, adeC, emrB, mexB and macAB) was enhanced in in vitro generated colistin-resistant strains. WGS of these organisms identified disruptions in genes involved in lipid A (lpxC) and phospholipid synthesis (mlaA), and in the baeS/R two-component system (TCS). We additionally found that mutations in the pmrB TCS genes were the primary colistin-resistance-associated mechanisms in three Vietnamese clinical colistin-resistant A. baumannii strains. Our results outline the entire range of mechanisms employed in A. baumannii for resistance against colistin, including drug extrusion and the loss of lipid A moieties by gene disruption or modification.

33. Lyse-Reseal Erythrocytes for Transfection of Plasmodium falciparum.

Author

Govindarajalu, Gokulapriya, Rizvi, Zeba, Kumar, Deepak, and Sijwali, Puran Singh

Subjects
ERYTHROCYTES, GENE transfection, PLASMODIUM falciparum, ELECTROPORATION, DNA
Abstract

Simple and efficient transfection methods for genetic manipulation of Plasmodium falciparum are desirable to identify, characterize and validate the genes with therapeutic potential and better understand parasite biology. Among the available transfection techniques for P. falciparum, electroporation-based methods, particularly electroporation of ring-infected RBCs is routinely used. Nonetheless, transfection of P. falciparum remains a resource-intensive procedure. Here, we report a simple and economic transfection method for P. falciparum, which is termed as the lyse-reseal erythrocytes for transfection (LyRET). It involved lysis of erythrocytes with a hypotonic RBC lysis buffer containing the desired plasmid DNA, followed by resealing by adding a high salt buffer. These DNA-encapsulated lyse-reseal erythrocytes were mixed with P. falciparum trophozoite/schizont stages and subjected to selection for the plasmid-encoded drug resistance. In parallel, transfections were also done by the methods utilizing electroporation of DNA into uninfected RBCs and parasite-infected RBCs. The LyRET method successfully transfected 3D7 and D10 strains with different plasmids in 63 of the 65 attempts, with success rate similar to transfection by electroporation of DNA into infected RBCs. The cost effectiveness and comparable efficiency of LyRET method makes it an alternative to the existing transfection methods for P. falciparum, particularly in resource-limited settings. [ABSTRACT FROM AUTHOR]

Published
2019
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34. Biosynthesis of heme O in intraerythrocytic stages of Plasmodium falciparum and potential inhibitors of this pathway.

Author

Simão-Gurge, Raquel M., Wunderlich, Gerhard, Cricco, Julia A., Cubillos, Eliana F. Galindo, Doménech-Carbó, Antonio, Cebrián-Torrejón, Gerardo, Almeida, Fernando G., Cirulli, Brenda A., and Katzin, Alejandro M.

Subjects
PLASMODIUM falciparum, BIOSYNTHESIS, HEME, ANTIMALARIALS, MASS spectrometry
Abstract

A number of antimalarial drugs interfere with the electron transport chain and heme-related reactions; however, the biosynthesis of heme derivatives in Plasmodium parasites has not been fully elucidated. Here, we characterized the steps that lead to the farnesylation of heme. After the identification of a gene encoding heme O synthase, we identified heme O synthesis in blood stage parasites through the incorporation of radioactive precursors. The presence of heme O synthesis in intraerythrocytic stages of Plasmodium falciparum was confirmed by mass spectrometry. Inabenfide and uniconazole–P appeared to interfere in heme synthesis, accordingly, parasite growth was also affected by the addition of these drugs. We conclude that heme O synthesis occurs in blood stage-P. falciparum and this pathway could be a potential target for antimalarial drugs. [ABSTRACT FROM AUTHOR]

Published
2019
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35. Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections.

Author

Cowell, Annie N. and Winzeler, Elizabeth A.

Subjects
PROTOZOAN diseases, PARASITIC diseases, MALARIA, PLASMODIUM, PLASMODIUM falciparum, DRUG design
Abstract

A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and gametocytes. A primary method for drug target deconvolution in Plasmodium falciparum is in vitro evolution of compound-resistant parasites followed by whole-genome scans. Several of the most promising antimalarial drug targets, such as translation elongation factor 2 (eEF2) and phenylalanine tRNA synthetase (PheRS), have been identified or confirmed using this method. One drawback of this method is that if a mutated gene is uncharacterized, a substantial effort may be required to determine whether it is a drug target, a drug resistance gene, or if the mutation is merely a background mutation. Thus, the availability of high-throughput, functional genomic datasets can greatly assist with target deconvolution. Studies mapping genome-wide essentiality in P. falciparum or performing transcriptional profiling of the host and parasite during liver-stage infection with P. berghei have identified potentially druggable pathways. Advances in mapping the epigenomic regulation of the malaria parasite genome have also enabled the identification of key processes involved in parasite development. In addition, the examination of the host genome during infection has identified novel gene candidates associated with susceptibility to severe malaria. Here, we review recent studies that have used omics-based methods to identify novel targets for interventions against protozoan parasites, focusing on malaria, and we highlight the advantages and limitations of the approaches used. These approaches have also been extended to other protozoan pathogens, including Toxoplasma, Trypanosoma, and Leishmania spp., and these studies highlight how drug discovery efforts against these pathogens benefit from the utilization of diverse omics-based methods to identify promising drug targets. [ABSTRACT FROM AUTHOR]

Published
2019
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36. Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor.

Author

Valenciano, Ana Lisa, Fernández-Murga, Maria L., Merino, Emilio F., Holderman, Nicole R., Butschek, Grant J., Shaffer, Karl J., Tyler, Peter C., and Cassera, Maria Belen

Subjects
CHORISMATE synthase, PLASMODIUM falciparum, UBIQUINONES, AMINOBENZOIC acids, BENZOQUINONES
Abstract

The shikimate pathway, a metabolic pathway absent in humans, is responsible for the production of chorismate, a branch point metabolite. In the malaria parasite, chorismate is postulated to be a direct precursor in the synthesis of p-aminobenzoic acid (folate biosynthesis), p-hydroxybenzoic acid (ubiquinone biosynthesis), menaquinone, and aromatic amino acids. While the potential value of the shikimate pathway as a drug target is debatable, the metabolic dependency of chorismate in P. falciparum remains unclear. Current evidence suggests that the main role of chorismate is folate biosynthesis despite ubiquinone biosynthesis being active and essential in the malaria parasite. Our goal in the present work was to expand our knowledge of the ubiquinone head group biosynthesis and its potential metabolic dependency on chorismate in P. falciparum. We systematically assessed the development of both asexual and sexual stages of P. falciparum in a defined medium in the absence of an exogenous supply of chorismate end-products and present biochemical evidence suggesting that the benzoquinone ring of ubiquinones in this parasite may be synthesized through a yet unidentified route. [ABSTRACT FROM AUTHOR]

Published
2019
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37. Plasmodium pseudo-Tyrosine Kinase-like binds PP1 and SERA5 and is exported to host erythrocytes.

Author

Gnangnon, Bénédicte, Fréville, Aline, Cailliau, Katia, Leroy, Catherine, De Witte, Caroline, Tulasne, David, Martoriarti, Alain, Jung, Vincent, Guerrera, Ida Chiara, Marion, Sabrina, Khalife, Jamal, and Pierrot, Christine

Abstract

Pseudokinases play key roles in many biological processes but they are poorly understood compared to active kinases. Eight putative pseudokinases have been predicted in Plasmodium species. We selected the unique pseudokinase belonging to tyrosine kinase like (TKL) family for detailed structural and functional analysis in P. falciparum and P. berghei. The primary structure of PfpTKL lacks residues critical for kinase activity, supporting its annotation as a pseudokinase. The recombinant pTKL pseudokinase domain was able to bind ATP, but lacked catalytic activity as predicted. The sterile alpha motif (SAM) and RVxF motifs of PfpTKL were found to interact with the P. falciparum proteins serine repeat antigen 5 (SERA5) and protein phosphatase type 1 (PP1) respectively, suggesting that pTKL has a scaffolding role. Furthermore, we found that PP1c activity in a heterologous model was modulated in an RVxF-dependent manner. During the trophozoite stages, PbpTKL was exported to infected erythrocytes where it formed complexes with proteins involved in cytoskeletal organization or host cell maturation and homeostasis. Finally, genetic analysis demonstrated that viable strains obtained by genomic deletion or knocking down PbpTKL did not affect the course of parasite intra-erythrocytic development or gametocyte emergence, indicating functional redundancy during these parasite stages. [ABSTRACT FROM AUTHOR]

Published
2019
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