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4. Dynamics of Host Immune Response Development During Schistosoma mansoni Infection

Author

Costain, A.H., Phythian-Adams, A.T., Colombo, S.A.P., Marley, A.K., Owusu, C., Cook, P.C., Brown, S.L., Webb, L.M., Lundie, R.J., Smits, H.H., Berriman, M., and MacDonald, A.S.

Subjects
schistosomiasis, Immunology, Immunology and Allergy, pathology, dendritic cells, chronic infection, transcriptomic (RNA-seq)
Abstract

Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+cells in dictating host immunopathology against this important helminth infection.

Published
2022

5. SARS-CoV-2 evolution during treatment of chronic infection

Author

Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Estee Torok, M., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Abnizova, I., Aigrain, L., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Betteridge, E., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Bonfield, J., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Goodwin, S., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Liddle, J., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Makunin, A., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mccarthy, S., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Puethe, C., Quail, M., Rajan, D., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Scott, C., Seekings, P., Shirley, L., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Jansen Van, P., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., Farr, B. W., Quail, M. A., Thurston, S. A. J., Bronner, I. F., Redshaw, N. M., Lensing, S. V., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Sharrocks, K., Blane, E., Modis, Y., Leigh, K. E., Briggs, J. A. G., van Gils, M. J., Smith, K. G. C., Bradley, J. R., Doffinger, R., Ceron-Gutierrez, L., Barcenas-Morales, G., Pollock, D. D., Goldstein, R. A., Smielewska, A., Skittrall, J. P., Gouliouris, T., Goodfellow, I. G., Gkrania-Klotsas, E., Illingworth, C. J. R., Mccoy, L. E., Gupta, R. K., Medical Microbiology and Infection Prevention, AII - Infectious diseases, Collier, Dami A [0000-0001-5446-4423], Jahun, Aminu [0000-0002-4585-1701], Temperton, Nigel [0000-0002-7978-3815], Modis, Yorgo [0000-0002-6084-0429], Briggs, John AG [0000-0003-3990-6910], Goldstein, Richard A [0000-0001-5148-4672], Skittrall, Jordan P [0000-0002-8228-3758], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], McCoy, Laura E [0000-0001-9503-7946], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, viruses, Passive, Antibodies, Viral, CITIID-NIHR BioResource COVID-19 Collaboration, 2.1 Biological and endogenous factors, Viral, Aetiology, Neutralizing, Lung, Phylogeny, neutralising antibodies, Infectivity, education.field_of_study, Genome, Multidisciplinary, Alanine, biology, High-Throughput Nucleotide Sequencing, Viral Load, Spike Glycoprotein, Virus Shedding, Adenosine Monophosphate, Aged, Antibodies, Neutralizing, COVID-19, Chronic Disease, Genome, Viral, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Mutagenesis, Mutant Proteins, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Evolution, Molecular, Infectious Diseases, Pneumonia & Influenza, Antibody, Infection, Viral load, Biotechnology, Evolution, General Science & Technology, antibody escape, Convalescent plasma, 030106 microbiology, Population, evasion, Antibodies, Virus, Article, Vaccine Related, resistance, 03 medical and health sciences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Biodefense, Genetics, Viral shedding, education, COVID-19 Serotherapy, QR355, Prevention, Wild type, Molecular, Pneumonia, Virology, COVID-19 Drug Treatment, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, biology.protein, Immunization, immune suppression, mutation
Abstract

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Published
2021

6. Long-read assembly and comparative evidence-based reanalysis of Cryptosporidium genome sequences reveal expanded transporter repertoire and duplication of entire chromosome ends including subtelomeric regions

Author

Baptista, RP, Li, Y, Sateriale, A, Sanders, MJ, Brooks, KL, Tracey, A, Ansell, BRE, Jex, AR, Cooper, GW, Smith, ED, Xiao, R, Dumaine, JE, Georgeson, P, Pope, BJ, Berriman, M, Striepen, B, Cotton, JA, Kissinger, JC, Baptista, RP, Li, Y, Sateriale, A, Sanders, MJ, Brooks, KL, Tracey, A, Ansell, BRE, Jex, AR, Cooper, GW, Smith, ED, Xiao, R, Dumaine, JE, Georgeson, P, Pope, BJ, Berriman, M, Striepen, B, Cotton, JA, and Kissinger, JC

Abstract

Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences hamper annotation, experimental design, and interpretation. We have generated a new C. parvum IOWA genome assembly supported by Pacific Biosciences (PacBio) and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species: C. parvum, Cryptosporidium hominis, and Cryptosporidium tyzzeri We made 1926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns, and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum, C. hominis, and C. tyzzeri revealed that most "missing" orthologs are found, suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation, and single-nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free, and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.

Published
2022

7. The gut microbial metabolic capacity of microbiome-humanized vs. wild type rodents reveals a likely dual role of intestinal bacteria in hepato-intestinal schistosomiasis.

Author

Downs, JA, Cortés, A, Martin, J, Rosa, BA, Stark, KA, Clare, S, McCarthy, C, Harcourt, K, Brandt, C, Tolley, C, Lawley, TD, Mitreva, M, Berriman, M, Rinaldi, G, Cantacessi, C, Downs, JA, Cortés, A, Martin, J, Rosa, BA, Stark, KA, Clare, S, McCarthy, C, Harcourt, K, Brandt, C, Tolley, C, Lawley, TD, Mitreva, M, Berriman, M, Rinaldi, G, and Cantacessi, C

Abstract

Increasing evidence shows that the host gut microbiota might be involved in the immunological cascade that culminates with the formation of tissue granulomas underlying the pathophysiology of hepato-intestinal schistosomiasis. In this study, we investigated the impact of Schistosoma mansoni infection on the gut microbial composition and functional potential of both wild type and microbiome-humanized mice. In spite of substantial differences in microbiome composition at baseline, selected pathways were consistently affected by parasite infection. The gut microbiomes of infected mice of both lines displayed, amongst other features, enhanced capacity for tryptophan and butyrate production, which might be linked to the activation of mechanisms aimed to prevent excessive injuries caused by migrating parasite eggs. Complementing data from previous studies, our findings suggest that the host gut microbiome might play a dual role in the pathophysiology of schistosomiasis, where intestinal bacteria may contribute to egg-associated pathology while, in turn, protect the host from uncontrolled tissue damage.

Published
2022

8. Genomic reconstruction of the SARS-CoV-2 epidemic in England

Author

Vöhringer, HS, Sanderson, T, Sinnott, M, De Maio, N, Nguyen, T, Goater, R, Schwach, F, Harrison, I, Hellewell, J, Ariani, CV, Gonçalves, S, Jackson, DK, Johnston, I, Jung, AW, Saint, C, Sillitoe, J, Suciu, M, Goldman, N, Panovska-Griffiths, J, Abnizova, I, Aigrain, L, Alderton, A, Ali, M, Allen, L, Amato, R, Anderson, R, Ariani, C, Austin-Guest, S, Bala, S, Barrett, J, Bassett, A, Battleday, K, Beal, J, Beale, M, Beaver, C, Bellany, S, Bellerby, T, Bellis, K, Berger, D, Berriman, M, Betteridge, E, Bevan, P, Binley, S, Bishop, J, Blackburn, K, Bonfield, J, Boughton, N, Bowker, S, Brendler-Spaeth, T, Bronner, I, Brooklyn, T, Buddenborg, SK, Bush, R, Caetano, C, Cagan, A, Carter, N, Cartwright, J, Monteiro, TC, Chapman, L, Chillingworth, T-J, Clapham, P, Clark, R, Clarke, A, Clarke, C, Cole, D, Cook, E, Coppola, M, Cornell, L, Cornwell, C, Corton, C, Crackett, A, Cranage, A, Craven, H, Craw, S, Crawford, M, Cutts, T, Dabrowska, M, Davies, M, Davies, R, Dawson, J, Day, C, Densem, A, Dibling, T, Dockree, C, Dodd, D, Dogga, S, Dorman, M, Dougan, G, Dougherty, M, Dove, A, Drummond, L, Drury, E, Dudek, M, Durham, J, Durrant, L, Easthope, E, Eckert, S, Ellis, P, Farr, B, Fenton, M, Ferrero, M, Flack, N, Fordham, H, Forsythe, G, Foulser, L, Francis, M, Fraser, A, Freeman, A, Galvin, A, Garcia-Casado, M, Gedny, A, Girgis, S, Glover, J, Goncalves, S, Goodwin, S, Gould, O, Gourtovaia, M, Gray, A, Gray, E, Griffiths, C, Gu, Y, Guerin, F, Hamilton, W, Hanks, H, Harrison, E, Harrott, A, Harry, E, Harvison, J, Heath, P, Hernandez-Koutoucheva, A, Hobbs, R, Holland, D, Holmes, S, Hornett, G, Hough, N, Huckle, L, Hughes-Hallet, L, Hunter, A, Inglis, S, Iqbal, S, Jackson, A, Jackson, D, James, K, Jamrozy, D, Verdejo, CJ, Jones, M, Kallepally, K, Kane, L, Kay, K, Kay, S, Keatley, J, Keith, A, King, A, Kitchin, L, Kleanthous, M, Klimekova, M, Korlevic, P, Krasheninnkova, K, Lane, G, Langford, C, Laverack, A, Law, K, Lawniczak, M, Lensing, S, Leonard, S, Letchford, L, Lewis, K, Lewis-Wade, A, Liddle, J, Lin, Q, Lindsay, S, Linsdell, S, Livett, R, Lo, S, Long, R, Lovell, J, Ludden, C, Mack, J, Maddison, M, Makunin, A, Mamun, I, Mansfield, J, Marriott, N, Martin, M, Mayho, M, McCarthy, S, McClintock, J, McGuigan, S, McHugh, S, McMinn, L, Meadows, C, Mobley, E, Moll, R, Morra, M, Morrow, L, Murie, K, Nash, S, Nathwani, C, Naydenova, P, Neaverson, A, Nelson, R, Nerou, E, Nicholson, J, Nimz, T, Noell, GG, O’Meara, S, Ohan, V, Oliver, K, Olney, C, Ormond, D, Oszlanczi, A, Palmer, S, Pang, YF, Pardubska, B, Park, N, Parmar, A, Patel, G, Patel, M, Payne, M, Peacock, S, Petersen, A, Plowman, D, Preston, T, Prestwood, L, Puethe, C, Quail, M, Rajan, D, Rajatileka, S, Rance, R, Rawlings, S, Redshaw, N, Reynolds, J, Reynolds, M, Rice, S, Richardson, M, Roberts, C, Robinson, K, Robinson, M, Robinson, D, Rogers, H, Rojo, EM, Roopra, D, Rose, M, Rudd, L, Sadri, R, Salmon, N, Saul, D, Scott, C, Seekings, P, Shirley, L, Simms, A, Sivadasan, S, Siwek, B, Sizer, D, Skeldon, K, Skelton, J, Slater-Tunstill, J, Sloper, L, Smerdon, N, Smith, C, Smith, J, Smith, K, Smith, M, Smith, S, Smith, T, Sneade, L, Soria, CD, Sousa, C, Souster, E, Sparkes, A, Spencer-Chapman, M, Squares, J, Stanley, R, Steed, C, Stickland, T, Still, I, Stratton, MR, Strickland, M, Swann, A, Swiatkowska, A, Sycamore, N, Swift, E, Symons, E, Szluha, S, Taluy, E, Tao, N, Taylor, K, Taylor, S, Thompson, S, Thompson, M, Thomson, M, Thomson, N, Thurston, S, Tonkin-Hill, G, Toombs, D, Topping, B, Tovar-Corona, J, Ungureanu, D, Uphill, J, Urbanova, J, Van Vuuren, PJ, Vancollie, V, Voak, P, Walker, D, Walker, M, Waller, M, Ward, G, Weatherhogg, C, Webb, N, Weldon, D, Wells, A, Wells, E, Westwood, L, Whipp, T, Whiteley, T, Whitton, G, Whitwham, A, Widaa, S, Williams, M, Wilson, M, Wright, S, Robson, SC, Connor, TR, Loman, NJ, Golubchik, T, Martinez Nunez, RT, Bonsall, D, Rambaut, A, Snell, LB, Corden, S, Nastouli, E, Nebbia, G, Lythgoe, K, Torok, ME, Goodfellow, IG, Prieto, JA, Saeed, K, Houlihan, C, Frampton, D, Hamilton, WL, Witney, AA, Bucca, G, Pope, CF, Moore, C, Thomson, EC, Harrison, EM, Smith, CP, Rogan, F, Beckwith, SM, Murray, A, Singleton, D, Eastick, K, Sheridan, LA, Randell, P, Jackson, LM, Fairley, DJ, Loose, MW, Watkins, J, Moses, S, Nicholls, S, Bull, M, Smith, DL, Aanensen, DM, Aggarwal, D, Shepherd, JG, Curran, MD, Parmar, S, Parker, MD, Williams, C, Glaysher, S, Underwood, AP, Bashton, M, Pacchiarini, N, Loveson, KF, Byott, M, Carabelli, AM, Templeton, KE, de Silva, TI, Wang, D, Langford, CF, Gunson, RN, Cottrell, S, O’Grady, J, Kwiatkowski, D, Lillie, PJ, Cortes, N, Moore, N, Thomas, C, Burns, PJ, Mahungu, TW, Liggett, S, Beckett, AH, Holden, MTG, Levett, LJ, Osman, H, Hassan-Ibrahim, MO, Simpson, DA, Chand, M, Gupta, RK, Darby, AC, Paterson, S, Pybus, OG, Volz, EM, de Angelis, D, Robertson, DL, Page, AJ, Bassett, AR, Wong, N, Taha, Y, Erkiert, MJ, Spencer Chapman, MH, Dewar, R, McHugh, MP, Mookerjee, S, Aplin, S, Harvey, M, Sass, T, Umpleby, H, Wheeler, H, McKenna, JP, Warne, B, Taylor, JF, Chaudhry, Y, Izuagbe, R, Jahun, AS, Young, GR, McMurray, C, McCann, CM, Nelson, A, Elliott, S, Lowe, H, Price, A, Crown, MR, Rey, S, Roy, S, Temperton, B, Shaaban, S, Hesketh, AR, Laing, KG, Monahan, IM, Heaney, J, Pelosi, E, Silviera, S, Wilson-Davies, E, Fryer, H, Adams, H, du Plessis, L, Johnson, R, Harvey, WT, Hughes, J, Orton, RJ, Spurgin, LG, Bourgeois, Y, Ruis, C, O’Toole, Á, Fraser, C, Edgeworth, J, Breuer, J, Michell, SL, Todd, JA, John, M, Buck, D, Gajee, K, Kay, GL, Peacock, SJ, Heyburn, D, Kitchman, K, McNally, A, Pritchard, DT, Dervisevic, S, Muir, P, Robinson, E, Vipond, BB, Ramadan, NA, Jeanes, C, Catalan, J, Jones, N, da Silva Filipe, A, Fuchs, M, Miskelly, J, Jeffries, AR, Park, NR, Ash, A, Koshy, C, Barrow, M, Buchan, SL, Mantzouratou, A, Clark, G, Holmes, CW, Campbell, S, Davis, T, Tan, NK, Brown, JR, Harris, KA, Kidd, SP, Grant, PR, Xu-McCrae, L, Cox, A, Madona, P, Pond, M, Randell, PA, Withell, KT, Graham, C, Denton-Smith, R, Swindells, E, Turnbull, R, Sloan, TJ, Bosworth, A, Hutchings, S, Pymont, HM, Casey, A, Ratcliffe, L, Jones, CR, Knight, BA, Haque, T, Hart, J, Irish-Tavares, D, Witele, E, Mower, C, Watson, LK, Collins, J, Eltringham, G, Crudgington, D, Macklin, B, Iturriza-Gomara, M, Lucaci, AO, McClure, PC, Carlile, M, Holmes, N, Storey, N, Rooke, S, Yebra, G, Craine, N, Perry, M, Alikhan, N-F, Bridgett, S, Cook, KF, Fearn, C, Goudarzi, S, Lyons, RA, Williams, T, Haldenby, ST, Davies, RM, Batra, R, Blane, B, Spyer, MJ, Smith, P, Yavus, M, Williams, RJ, Mahanama, AIK, Samaraweera, B, Girgis, ST, Hansford, SE, Green, A, Bellis, KL, Dorman, MJ, Quick, J, Poplawski, R, Reynolds, N, Mack, A, Morriss, A, Whalley, T, Patel, B, Georgana, I, Hosmillo, M, Pinckert, ML, Stockton, J, Henderson, JH, Hollis, A, Stanley, W, Yew, WC, Myers, R, Thornton, A, Adams, A, Annett, T, Asad, H, Birchley, A, Coombes, J, Evans, JM, Fina, L, Gatica-Wilcox, B, Gilbert, L, Graham, L, Hey, J, Hilvers, E, Jones, S, Jones, H, Kumziene-Summerhayes, S, McKerr, C, Powell, J, Pugh, G, Trotter, AJ, Williams, CA, Kermack, LM, Foulkes, BH, Gallis, M, Hornsby, HR, Louka, SF, Pohare, M, Wolverson, P, Zhang, P, MacIntyre-Cockett, G, Trebes, A, Moll, RJ, Ferguson, L, Goldstein, EJ, Maclean, A, Tomb, R, Starinskij, I, Thomson, L, Southgate, J, Kraemer, MUG, Raghwani, J, Zarebski, AE, Boyd, O, Geidelberg, L, Illingworth, CJ, Jackson, C, Pascall, D, Vattipally, S, Freeman, TM, Hsu, SN, Lindsey, BB, Tovar-Corona, JM, Cox, M, Abudahab, K, Menegazzo, M, Taylor, BEW, Yeats, CA, Mukaddas, A, Wright, DW, de Oliveira Martins, L, Colquhoun, R, Hill, V, Jackson, B, McCrone, JT, Medd, N, Scher, E, Keatley, J-P, Curran, T, Morgan, S, Maxwell, P, Eldirdiri, S, Kenyon, A, Holmes, AH, Price, JR, Wyatt, T, Mather, AE, Skvortsov, T, Hartley, JA, Guest, M, Kitchen, C, Merrick, I, Munn, R, Bertolusso, B, Lynch, J, Vernet, G, Kirk, S, Wastnedge, E, Idle, G, Bradley, DT, Poyner, J, Mori, M, Jones, O, Wright, V, Brooks, E, Churcher, CM, Fragakis, M, Galai, K, Jermy, A, Judges, S, McManus, GM, Smith, KS, Westwick, E, Attwood, SW, Bolt, F, Davies, A, De Lacy, E, Downing, F, Edwards, S, Meadows, L, Jeremiah, S, Smith, N, Charalampous, T, Patel, A, Berry, L, Boswell, T, Fleming, VM, Howson-Wells, HC, Joseph, A, Khakh, M, Lister, MM, Bird, PW, Fallon, K, Helmer, T, McMurray, CL, Odedra, M, Shaw, J, Tang, JW, Willford, NJ, Blakey, V, Raviprakash, V, Sheriff, N, Williams, L-A, Feltwell, T, Bedford, L, Cargill, JS, Hughes, W, Moore, J, Stonehouse, S, Atkinson, L, Lee, JCD, Shah, D, Alcolea, A, Ohemeng-Kumi, N, Ramble, J, Sehmi, J, Williams, R, Chatterton, W, Pusok, M, Everson, W, Castigador, A, Macnaughton, E, El Bouzidi, K, Lampejo, T, Sudhanva, M, Breen, C, Sluga, G, Ahmad, SSY, George, RP, Machin, NW, Binns, D, James, V, Blacow, R, Coupland, L, Smith, L, Barton, E, Padgett, D, Scott, G, Cross, A, Mirfenderesky, M, Greenaway, J, Cole, K, Clarke, P, Duckworth, N, Walsh, S, Bicknell, K, Impey, R, Wyllie, S, Hopes, R, Bishop, C, Chalker, V, Gifford, L, Molnar, Z, Auckland, C, Evans, C, Johnson, K, Partridge, DG, Raza, M, Baker, P, Bonner, S, Essex, S, Murray, LJ, Lawton, AI, Burton-Fanning, S, Payne, BAI, Waugh, S, Gomes, AN, Kimuli, M, Murray, DR, Ashfield, P, Dobie, D, Ashford, F, Best, A, Crawford, L, Cumley, N, Mayhew, M, Megram, O, Mirza, J, Moles-Garcia, E, Percival, B, Ensell, L, Lowe, HL, Maftei, L, Mondani, M, Chaloner, NJ, Cogger, BJ, Easton, LJ, Huckson, H, Lewis, J, Lowdon, S, Malone, CS, Munemo, F, Mutingwende, M, Nicodemi, R, Podplomyk, O, Somassa, T, Beggs, A, Richter, A, Cormie, C, Dias, J, Forrest, S, Higginson, EE, Maes, M, Young, J, Davidson, RK, Jackson, KA, Turtle, L, Keeley, AJ, Ball, J, Byaruhanga, T, Chappell, JG, Dey, J, Hill, JD, Park, EJ, Fanaie, A, Hilson, RA, Yaze, G, Afifi, S, Beer, R, Maksimovic, J, Masters, KM, Spellman, K, Bresner, C, Fuller, W, Marchbank, A, Workman, T, Shelest, E, Debebe, J, Sang, F, Zamudio, ME, Francois, S, Gutierrez, B, Vasylyeva, TI, Flaviani, F, Ragonnet-Cronin, M, Smollett, KL, Broos, A, Mair, D, Nichols, J, Nomikou, K, Tong, L, Tsatsani, I, O’Brien, S, Rushton, S, Sanderson, R, Perkins, J, Cotton, S, Gallagher, A, Allara, E, Pearson, C, Bibby, D, Dabrera, G, Ellaby, N, Gallagher, E, Hubb, J, Lackenby, A, Lee, D, Manesis, N, Mbisa, T, Platt, S, Twohig, KA, Morgan, M, Aydin, A, Baker, DJ, Foster-Nyarko, E, Prosolek, SJ, Rudder, S, Baxter, C, Carvalho, SF, Lavin, D, Mariappan, A, Radulescu, C, Singh, A, Tang, M, Morcrette, H, Bayzid, N, Cotic, M, Balcazar, CE, Gallagher, MD, Maloney, D, Stanton, TD, Williamson, KA, Manley, R, Michelsen, ML, Sambles, CM, Studholme, DJ, Warwick-Dugdale, J, Eccles, R, Gemmell, M, Gregory, R, Hughes, M, Nelson, C, Rainbow, L, Vamos, EE, Webster, HJ, Whitehead, M, Wierzbicki, C, Angyal, A, Green, LR, Whiteley, M, Bronner, IF, Farr, BW, Lensing, SV, McCarthy, SA, Quail, MA, Redshaw, NM, Thurston, SAJ, Rowe, W, Gaskin, A, Le-Viet, T, Birney, E, Volz, E, Funk, S, Martincorena, I, Barrett, JC, and Gerstung, M

Abstract

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.

Published
2021

9. Genomic landscape of drug response reveals mediators of anthelmintic resistance

Author

Doyle, S.R., Laing, R, Bartley, David, Morrison, A., Holroyd, N., Maitland , K., Antonopoulos, A., Britton, C., Chaudhry, Umer, Flis , I., Howell, S., McIntyre, J., Gilleard, J.S., Tait , A., Mable , B., Kaplan, R., Sargison, Neil, Berriman , M., Devaney, E, and Cotton, J.

Subjects
Anthelmintics, Ivermectin, Drug Resistance/genetics, Ivermectin/pharmacology, Levamisole, Anthelmintics/pharmacology, Drug Resistance, Benzimidazoles, Genomics, General Biochemistry, Genetics and Molecular Biology, Transcription Factors
Abstract

Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

Published
2022

10. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Author

Collier, D. A., De Marco, A., Ferreira, I. A. T. M., Meng, B., Datir, R. P., Walls, A. C., Kemp, S. A., Bassi, J., Pinto, D., Silacci-Fregni, C., Bianchi, S., Tortorici, M. A., Bowen, J., Culap, K., Jaconi, S., Cameroni, E., Snell, G., Pizzuto, M. S., Pellanda, A. F., Garzoni, C., Riva, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Mccoy, L. E., Smith, K. G. C., Bradley, J. R., Temperton, N., Ceron-Gutierrez, L., Barcenas-Morales, G., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Torok, M. E., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., Hosmillo, M., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., Mccarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Bonfield, J., Puethe, C., Whitwham, A., Liddle, J., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Abnizova, I., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Quail, M., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Seekings, P., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Van, P. J., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Widaa, S., Williams, M., Wilson, M., Wright, S., Harvey, W., Virgin, H. W., Lanzavecchia, A., Piccoli, L., Doffinger, R., Wills, M., Veesler, D., Corti, D., and Gupta, R. K.

Subjects
0301 basic medicine, Male, Models, Molecular, Passive, Antibodies, Viral, Neutralization, 0302 clinical medicine, Models, Monoclonal, 80 and over, Viral, Neutralizing antibody, Neutralizing, Aged, 80 and over, Vaccines, Vaccines, Synthetic, Multidisciplinary, biology, Antibodies, Monoclonal, C500, Middle Aged, C700, Spike Glycoprotein, Vaccination, Spike Glycoprotein, Coronavirus, Female, Angiotensin-Converting Enzyme 2, Antibody, Aged, Antibodies, Neutralizing, COVID-19, COVID-19 Vaccines, HEK293 Cells, Humans, Immune Evasion, Immunization, Passive, Mutation, Neutralization Tests, SARS-CoV-2, medicine.drug_class, B100, Monoclonal antibody, Antibodies, Virus, 03 medical and health sciences, Immune system, medicine, COVID-19 Serotherapy, QR355, Synthetic, Molecular, Virology, Coronavirus, 030104 developmental biology, Immunization, biology.protein, 030217 neurology & neurosurgery
Abstract

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Published
2021

11. The Gene Ontology resource: enriching a GOld mine

Author

Carbon, S, Douglass, E, Good, Bm, Unni, Dr, Harris, Nl, Mungall, Cj, Basu, S, Chisholm, Rl, Dodson, Rj, Hartline, E, Fey, P, Thomas, Pd, Albou, Lp, Ebert, D, Kesling, Mj, Mi, Hy, Muruganujan, A, Huang, Xs, Mushayahama, T, Labonte, Sa, Siegele, Da, Antonazzo, G, Attrill, H, Brown, Nh, Garapati, P, Marygold, Sj, Trovisco, V, Dos Santos, G, Falls, K, Tabone, C, Zhou, Pl, Goodman, Jl, Strelets, Vb, Thurmond, J, Garmiri, P, Ishtiaq, R, Rodriguez-Lopez, M, Acencio, Ml, Kuiper, M, Laegreid, A, Logie, C, Lovering, Rc, Kramarz, B, Saverimuttu, Scc, Pinheiro, Sm, Gunn, H, Su, Rz, Thurlow, Ke, Chibucos, M, Giglio, M, Nadendla, S, Munro, J, Jackson, R, Duesbury, Mj, Del-Toro, N, Meldal, Bhm, Paneerselvam, K, Perfetto, L, Porras, P, Orchard, S, Shrivastava, A, Chang, Hy, Finn, Rd, Mitchell, Al, Rawlings, Nd, Richardson, L, Sangrador-Vegas, A, Blake, Ja, Christie, Kr, Dolan, Me, Drabkin, Hj, Hill, Dp, Ni, L, Sitnikov, Dm, Harris, Ma, Oliver, Sg, Rutherford, K, Wood, V, Hayles, J, Bahler, J, Bolton, Er, De Pons JL, Dwinell, Mr, Hayman, Gt, Kaldunski, Ml, Kwitek, Ae, Laulederkind, Sjf, Plasterer, C, Tutaj, Ma, Vedi, M, Wang, Sj, D'Eustachio, P, Matthews, L, Balhoff, Jp, Aleksander, Sa, Alexander, Mj, Cherry, Jm, Engel, Sr, Gondwe, F, Karra, K, Miyasato, Sr, Nash, Rs, Simison, M, Skrzypek, Ms, Weng, S, Wong, Ed, Feuermann, M, Gaudet, P, Morgat, A, Bakker, E, Berardini, Tz, Reiser, L, Subramaniam, S, Huala, E, Arighi, Cn, Auchincloss, A, Axelsen, K, Argoud-Puy, G, Bateman, A, Blatter, Mc, Boutet, E, Bowler, E, Breuza, L, Bridge, A, Britto, R, Bye-A-Jee, H, Casas, Cc, Coudert, E, Denny, P, Estreicher, A, Famiglietti, Ml, Georghiou, G, Gos, A, Gruaz-Gumowski, N, Hatton-Ellis, E, Hulo, C, Ignatchenko, A, Jungo, F, Laiho, K, Le Mercier, P, Lieberherr, D, Lock, A, Lussi, Y, Macdougall, A, Magrane, M, Martin, Mj, Masson, P, Natale, Da, Hyka-Nouspikel, N, Pedruzzi, I, Pourcel, L, Poux, S, Pundir, S, Rivoire, C, Speretta, E, Sundaram, S, Tyagi, N, Warner, K, Zaru, R, Wu, Ch, Diehl, Ad, Chan, Jn, Grove, C, Lee, Ryn, Muller, Hm, Raciti, D, Van Auken, K, Sternberg, Pw, Berriman, M, Paulini, M, Howe, K, Gao, S, Wright, A, Stein, L, Howe, Dg, Toro, S, Westerfield, M, Jaiswal, P, Cooper, L, and Elser, J

Subjects
Traceability, AcademicSubjects/SCI00010, Arabidopsis, Saccharomyces cerevisiae, Biology, Ontology (information science), Gene Ontology, Data curation, GO-CAMs, World Wide Web, Mice, User-Computer Interface, 03 medical and health sciences, Consistency (database systems), Annotation, 0302 clinical medicine, Documentation, Resource (project management), Schema (psychology), Schizosaccharomyces, Escherichia coli, Genetics, Database Issue, Animals, Humans, Dictyostelium, Caenorhabditis elegans, Molecular Biology, Zebrafish, 030304 developmental biology, Internet, 0303 health sciences, Molecular Sequence Annotation, File format, Rats, Drosophila melanogaster, 030217 neurology & neurosurgery
Abstract

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20 000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations.

Published
2021

12. Extracellular non-coding RNA signatures of the metacestode stage of Echinococcus multilocularis

Author

Ancarola ME, Lichtenstein G, Herbig J, Holroyd N, Mariconti M, Brunetti E, Berriman M, Albrecht K, Marcilla A, Rosenzvit MC, Kamenetzky L, Brehm K, and Cucher M

Abstract

Extracellular RNAs (ex-RNAs) are secreted by cells through different means that may involve association with proteins, lipoproteins or extracellular vesicles (EV). In the context of parasitism, ex-RNAs represent new and exciting communication intermediaries with promising potential as novel biomarkers. In the last years, it was shown that helminth parasites secrete ex-RNAs, however, most work mainly focused on RNA secretion mediated by EV. Ex-RNA study is of special interest in those helminth infections that still lack biomarkers for early and/or follow-up diagnosis, such as echinococcosis, a neglected zoonotic disease caused by cestodes of the genus Echinococcus. In this work, we have characterised the ex-RNA profile secreted by in vitro grown metacestodes of Echinococcus multilocularis, the casuative agent of alveolar echinococcosis. We have used high throughput RNA-sequencing together with RT-qPCR to characterise the ex-RNA profile secreted towards the extra- and intra-parasite milieus in EV-enriched and EV-depleted fractions. We show that a polarized secretion of small RNAs takes place, with microRNAs mainly secreted to the extra-parasite milieu and rRNA- and tRNA-derived sequences mostly secreted to the intra-parasite milieu. In addition, we show by nanoparticle tracking analyses that viable metacestodes secrete EV mainly into the metacestode inner vesicular fluid (MVF); however, the number of nanoparticles in culture medium and MVF increases > 10-fold when metacestodes show signs of tegument impairment. Interestingly, we confirm the presence of host miRNAs in the intra-parasite milieu, implying their internalization and transport through the tegument towards the MVF. Finally, our assessment of the detection of Echinococcus miRNAs in patient samples by RT-qPCR yielded negative results suggesting the tested miRNAs may not be good biomarkers for this disease. A comprehensive study of the secretion mechanisms throughout the life cycle of these parasites will help to understand parasite interaction with the host and also, improve current diagnostic tools.

Published
2020

13. Baseline Gut Microbiota Composition Is Associated With Schistosoma mansoni Infection Burden in Rodent Models.

Author

Cortés, A, Clare, S, Costain, A, Almeida, A, McCarthy, C, Harcourt, K, Brandt, C, Tolley, C, Rooney, J, Berriman, M, Lawley, T, MacDonald, AS, Rinaldi, G, Cantacessi, C, Cortés, A, Clare, S, Costain, A, Almeida, A, McCarthy, C, Harcourt, K, Brandt, C, Tolley, C, Rooney, J, Berriman, M, Lawley, T, MacDonald, AS, Rinaldi, G, and Cantacessi, C

Abstract

In spite of growing evidence supporting the occurrence of complex interactions between Schistosoma and gut bacteria in mice and humans, no data is yet available on whether worm-mediated changes in microbiota composition are dependent on the baseline gut microbial profile of the vertebrate host. In addition, the impact of such changes on the susceptibility to, and pathophysiology of, schistosomiasis remains largely unexplored. In this study, mice colonized with gut microbial populations from a human donor (HMA mice), as well as microbiota-wild type (WT) animals, were infected with Schistosoma mansoni, and alterations of their gut microbial profiles at 50 days post-infection were compared to those occurring in uninfected HMA and WT rodents, respectively. Significantly higher worm and egg burdens, together with increased specific antibody responses to parasite antigens, were observed in HMA compared to WT mice. These differences were associated to extensive dissimilarities between the gut microbial profiles of each HMA and WT groups of mice at baseline; in particular, the gut microbiota of HMA animals was characterized by low microbial alpha diversity and expanded Proteobacteria, as well as by the absence of putative immunomodulatory bacteria (e.g. Lactobacillus). Furthermore, differences in infection-associated changes in gut microbiota composition were observed between HMA and WT mice. Altogether, our findings support the hypothesis that susceptibility to S.mansoni infection in mice is partially dependent on the composition of the host baseline microbiota. Moreover, this study highlights the applicability of HMA mouse models to address key biological questions on host-parasite-microbiota relationships in human helminthiases.

Published
2020

14. The genome of the social amoeba Dictyostelium discoideum

Author

Eichinger, L., Pachebat, J. A., Glöckner, G., Rajandream, M.-A., Sucgang, R., Berriman, M., Song, J., Olsen, R., Szafranski, K., Xu, Q., Tunggal, B., Kummerfeld, S., Madera, M., Konfortov, B. A., Rivero, F., Bankier, A. T., Lehmann, R., Hamlin, N., Davies, R., Gaudet, P., Fey, P., Pilcher, K., Chen, G., Saunders, D., Sodergren, E., Davis, P., Kerhornou, A., Nie, X., Hall, N., Anjard, C., Hemphill, L., Bason, N., Farbrother, P., Desany, B., Just, E., Morio, T., Rost, R., Churcher, C., Cooper, J., Haydock, S., van Driessche, N., Cronin, A., Goodhead, I., Muzny, D., Mourier, T., Pain, A., Lu, M., Harper, D., Lindsay, R., Hauser, H., James, K., Quiles, M., Madan Babu, M., Saito, T., Buchrieser, C., Wardroper, A., Felder, M., Thangavelu, M., Johnson, D., Knights, A., Loulseged, H., Mungall, K., Oliver, K., Price, C., Quail, M. A., Urushihara, H., Hernandez, J., Rabbinowitsch, E., Steffen, D., Sanders, M., Ma, J., Kohara, Y., Sharp, S., Simmonds, M., Spiegler, S., Tivey, A., Sugano, S., White, B., Walker, D., Woodward, J., Winckler, T., Tanaka, Y., Shaulsky, G., Schleicher, M., Weinstock, G., Rosenthal, A., Cox, E. C., Chisholm, R. L., Gibbs, R., Loomis, W. F., Platzer, M., Kay, R. R., Williams, J., Dear, P. H., Noegel, A. A., Barrell, B., and Kuspa, A.

Published
2005
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15. Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13

Author

Hall, N., Pain, A., Berriman, M., Churcher, C., Harris, B., Harris, D., Mungall, K., Bowman, S., Atkin, R., Baker, S., Barron, A., Brooks, K., Buckee, C. O., Burrows, C., Cherevach, I., Chillingworth, C., Chillingworth, T., Christodoulou, Z., Clark, L., Clark, R., Corton, C., Cronin, A., Davies, R., Davis, P., Dear, P., Dearden, F., Doggett, J., Feltwell, T., Goble, A., Goodhead, I., Gwilliam, R., Hamlin, N., Hance, Z., Harper, D., Hauser, H., Hornsby, T., Holroyd, S., Horrocks, P., Humphray, S., Jagels, K., James, K. D., Johnson, D., Kerhornou, A., Knights, A., Konfortov, B., Kyes, S., Larke, N., Lawson, D., Lennard, N., Line, A., Maddison, M., McLean, J., Mooney, P., Moule, S., Murphy, L., Oliver, K., Ormond, D., Price, C., Quail, M. A., Rabbinowitsch, E., Rajandream, M.-A., Rutter, S., Rutherford, K. M., Sanders, M., Simmonds, M., Seeger, K., Sharp, S., Smith, R., Squares, R., Squares, S., Stevens, K., Taylor, K., Tivey, A., Unwin, L., Whitehead, S., Woodward, J., Sulston, J. E., Craig, A., Newbold, C., and Barrell, B. G.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): N. Hall (corresponding author) [1]; A. Pain [1]; M. Berriman [1]; C. Churcher [1]; B. Harris [1]; D. Harris [1]; K. Mungall [1]; S. Bowman [1, 2]; R. Atkin [...]

Published
2002
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17. An integrated national scale SARS-CoV-2 genomic surveillance network

Author

Aanensen, DM, Abudahab, K, Adams, A, Afifi, S, Alam, MT, Alderton, A, Alikhan, N-F, Allan, J, Almsaud, M, Alrezaihi, A, Alruwaili, M, Amato, R, Andersson, M, Angyal, A, Aranday-Cortes, E, Ariani, C, Armstrong, SD, Asamaphan, P, Attwood, S, Aydin, A, Badhan, A, Baker, D, Baker, P, Balcazar, CE, Ball, J, Barton, AE, Bashton, M, Baxter, L, Beale, M, Beaver, C, Beckett, A, Beer, R, Beggs, A, Bell, A, Bellis, KL, Bentley, EG, Berriman, M, Betteridge, E, Bibby, D, Bicknell, K, Birchley, A, Black, G, Blane, B, Bloomfield, S, Bolt, F, Bonsall, DG, Bosworth, A, Bourgeois, Y, Boyd, O, Bradshaw, D, Breuer, J, Bridgewater, H, Brooks, T, Broos, A, Brown, JR, Brown, RL, Brunker, K, Bucca, G, Buck, D, Bull, M, Butcher, E, Caddy, SL, Caller, LG, Cambell, S, Carlile, M, Carmichael, S, Carrilero, L, Castellano, S, Chaloner, J, Chand, M, Chapman, MR, Chappell, J, Charles, I, Chauhan, AJ, Chawla, A, Cheng, E, Churcher, CM, Clark, G, Clark, JJ, Collins, J, Colquhoun, R, Connor, TR, Constantinidou, C, Coombes, J, Corden, S, Cottrell, S, Cowell, A, Curran, MD, Curran, T, Dabrera, G, Danesh, J, Darby, AC, De Cesare, M, Martins, LDO, De Silva, TI, Debebe, B, Dervisevic, S, Dewar, RA, Dia, M, Dorman, M, Dougan, G, Dover, L, Downing, F, Drury, E, Du Plessis, L, Dyal, PL, Eccles, R, Edwards, S, Ellaby, N, Elliott, S, Eltringham, G, Elumogo, N, Essex, S, Evans, CM, Evans, J, Nascimento, FF, Fairley, DJ, Farr, B, Feltwell, T, Ferguson, N, Filipe, ADS, Findlay, J, Forrest, LM, Forrest, S, Foulser, L, Francois, S, Fraser, C, Frost, L, Gallagher, E, Gallagher, MD, Garcia-Dorival, I, Gaskin, A, Gatica-Wilcox, B, Gavriil, A, Geidelberg, L, Gemmell, M, Gerada, A, Gifford, L, Gilbert, L, Gilmore, P, Gilroy, R, Girgis, S, Glaysher, S, Golubchik, T, Goncalves, S, Goodfellow, I, Goodwin, S, Graham, C, Graham, L, Grammatopoulos, D, Green, A, Green, LR, Greenaway, J, Gregory, R, Groves, DC, Groves, N, Guest, M, Gunson, R, Haldenby, S, Hall, G, Hamilton, WL, Han, X, Harris, KA, Harrison, EM, Hartley, C, Herrera, C, Hesketh, A, Heyburn, D, Hill, V, Hiscox, JA, Holden, M, Holmes, A, Holmes, N, Holt, GS, Hopes, R, Hosmillo, M, Houldcroft, CJ, Howson-Wells, H, Hubb, J, Hughe, J, Hughes, M, Hutchings, S, Impey, R, Iturriza-Gomara, M, Jackson, A, Jackson, B, Jackson, DK, Jahun, AS, James, K, Jamrozy, D, Jeffries, A, Jesudason, N, John, M, Johnson, J, Johnson, KJ, Johnson, N, Johnston, I, Jones, B, Jones, R, Jones, S, Jorgensen, D, Kane, L, Kay, GL, Kay, S, Keatley, J-P, Keeley, AJ, Khakh, M, Khokhar, FA, Kitchen, C, Knight, B, Kolyva, A, Kraemer, M, Kristiansen, M, Kumziene-Summerhayes, S, Kwiatkowski, D, Lackenby, A, Langford, C, Lawniczak, M, Thanh, L-V, Lee, D, Letchford, L, Li, K, Li, L, Liggett, S, Lindsey, BB, Livett, R, Lloyd, A, Lo, S, Lockhart, M, Loh, J, Loman, NJ, Loose, M, Lucaci, A, Ludden, C, Luu, L, Lyons, RA, MacIntyre-Cockett, G, MacLean, A, Mair, D, Maksimovic, J, Manley, R, Manso, C, Manson, J, Martincorena, I, Masoli, J, Mather, AE, Mbisa, T, McCluggage, K, McClure, P, McCrone, JT, McDonald, S, McHugh, MP, McKenna, JM, McMinn, L, McMurray, C, Meadows, L, Menegazzo, M, Meredith, LW, Merrick, I, Mestek-Boukhibar, L, Miah, S, Michell, S, Michelsen, ML, Molnar, Z, Moore, C, Moore, N, Morgan, M, Morgan, S, Muddyman, D, Muir, DA, Muir, P, Myers, R, Nastouli, E, Naydenova, P, Nelson, A, Nelson, C, Nelson, R, Nicholls, S, Nichols, J, Niebel, M, Niola, P, Nomikou, K, O'Grady, J, O'Toole, AN, O'Toole, E, Olateju, C, Orton, RJ, Osman, H, Ott, S, Pacchiarini, N, Padgett, D, Page, AJ, Palmer, S, Panchbhaya, YN, Pandey, S, Park, N, Parker, MD, Parkhill, J, Parr, YA, Parsons, PJ, Partridge, DG, Patel, M, Patterson, S, Payne, B, Peacock, SJ, Penrice-Randal, R, Perry, M, Platt, S, Poplawski, R, Prakash, R, Prestwood, L, Price, A, Price, JR, Puethe, C, Pybus, O, Pymont, H, Quail, M, Quick, J, Raghwani, J, Ragonnet-Cronin, M, Rahman, S, Rainbow, L, Rajatileka, S, Rambaut, A, Ramsay, M, Randell, PA, Randle, NP, Raviprakash, V, Raza, M, Silva, PR, Rey, S, Richter, A, Robertson, DL, Robinson, TI, Robson, SC, Rooke, S, Rowan, A, Rowe, W, Roy, S, Rudder, S, Ruis, C, Sang, F, Scarlett, G, Schaefer, U, Scott, C, Scott, G, Sethi, D, Shaaban, S, Shah, R, Sharma, P, Shawli, GT, Shepherd, J, Sherriff, N, Shirley, L, Sillitoe, J, Simpson, DA, Singer, JB, Siveroni, I, Smith, C, Smith, CP, Smith, DL, Smith, N, Smith, W, Smith-Palmer, A, Smollett, K, Southgate, J, Spellman, K, Spencer-Chapman, M, Sridhar, S, Stanley, R, Stark, R, Stewart, JP, Stockton, J, Stuart, C, Studholme, D, Swainston, N, Swindells, E, Taha, Y, Tariq, MA, Taylor, B, Taylor, GP, Taylor, S, Taylor-Joyce, G, Tedim, AP, Temperton, B, Templeton, KE, Thomson, EC, Thomson, NM, Thornton, A, Thurston, S, Todd, J, Tong, L, Tonkin-Hill, G, Torok, ME, Trebes, A, Trotter, AJ, Tsoleridis, T, Tucker, RM, Tutill, HJ, Underwood, A, Unnikrishnan, M, Vamos, E, Vasylyeva, T, Vattipally, S, Victoria, A, Vipond, B, Volz, EM, Wain, J, Wang, D, Warwick-Dugdale, J, Wastnedge, E, Watkins, J, Watts, J, Webber, M, Weeks, S, Weldon, D, Whitehead, M, Williams, CA, Williams, C, Williams, D, Williams, R, Williams, TC, Wise, E, Wright, V, Wyles, MD, Wyllie, S, Yakovleva, A, Yasir, M, Yeats, C, Yew, WC, Young, GR, Yu, X, and Zarebski, A

Subjects
Microbiology (medical), Scale (ratio), SARS-CoV-2, viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, COVID-19 Genomics UK (COG-UK) consortiumcontact@cogconsortium.uk, C500, Genome, Viral, Genomics, Biology, C700, Microbiology, Article, Infectious Diseases, Virology, Humans, Cartography
Abstract

The Coronavirus Disease 2019 (COVID-19) Genomics UK Consortium (COG-UK) was launched in March, 2020, with £20 million support from UK Research and Innovation, the UK Department of Health and Social Care, and Wellcome Trust. The goal of this consortium is to sequence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for up to 230 000 patients, health-care workers, and other essential workers in the UK with COVID-19, which will help to enable the tracking of SARS-CoV-2 transmission, identify viral mutations, and integrate with health data to assess how the viral genome interacts with cofactors and consequences of COVID-19.

Published
2020

18. The genome of the simian and human malaria parasite Plasmodium knowlesi

Author

Pain, A., Böhme, U., Berry, A. E., Mungall, K., Finn, R. D., Jackson, A. P., Mourier, T., Mistry, J., Pasini, E. M., Aslett, M. A., Balasubrammaniam, S., Borgwardt, K., Brooks, K., Carret, C., Carver, T. J., Cherevach, I., Chillingworth, T., Clark, T. G., Galinski, M. R., Hall, N., Harper, D., Harris, D., Hauser, H., Ivens, A., Janssen, C. S., Keane, T., Larke, N., Lapp, S., Marti, M., Moule, S., Meyer, I. M., Ormond, D., Peters, N., Sanders, M., Sanders, S., Sargeant, T. J., Simmonds, M., Smith, F., Squares, R., Thurston, S., Tivey, A. R., Walker, D., White, B., Zuiderwijk, E., Churcher, C., Quail, M. A., Cowman, A. F., Turner, C. M. R., Rajandream, M. A., Kocken, C. H. M., Thomas, A. W., Newbold, C. I., Barrell, B. G., and Berriman, M.

Published
2008
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24. Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution

Author

Rutledge, GG, Bohme, U, Sanders, M, Rrid, AJ, Cotton, JA, Maiga-Ascofare, O, Djimde, AA, Apinjoh, TO, Amenga-Etego, L, Manske, M, Barnwell, JW, Renaud, F, Ollomo, B, Prugnolle, F, Anstey, NM, Auburn, S, Price, RN, McCarthy, JS, Kwiatkowski, DP, Newbold, CI, Berriman, M, Otto, TD, Rutledge, GG, Bohme, U, Sanders, M, Rrid, AJ, Cotton, JA, Maiga-Ascofare, O, Djimde, AA, Apinjoh, TO, Amenga-Etego, L, Manske, M, Barnwell, JW, Renaud, F, Ollomo, B, Prugnolle, F, Anstey, NM, Auburn, S, Price, RN, McCarthy, JS, Kwiatkowski, DP, Newbold, CI, Berriman, M, and Otto, TD

Abstract

Elucidation of the evolutionary history and interrelatedness of Plasmodium species that infect humans has been hampered by a lack of genetic information for three human-infective species: P. malariae and two P. ovale species (P. o. curtisi and P. o. wallikeri). These species are prevalent across most regions in which malaria is endemic and are often undetectable by light microscopy, rendering their study in human populations difficult. The exact evolutionary relationship of these species to the other human-infective species has been contested. Using a new reference genome for P. malariae and a manually curated draft P. o. curtisi genome, we are now able to accurately place these species within the Plasmodium phylogeny. Sequencing of a P. malariae relative that infects chimpanzees reveals similar signatures of selection in the P. malariae lineage to another Plasmodium lineage shown to be capable of colonization of both human and chimpanzee hosts. Molecular dating suggests that these host adaptations occurred over similar evolutionary timescales. In addition to the core genome that is conserved between species, differences in gene content can be linked to their specific biology. The genome suggests that P. malariae expresses a family of heterodimeric proteins on its surface that have structural similarities to a protein crucial for invasion of red blood cells. The data presented here provide insight into the evolution of the Plasmodium genus as a whole.

Published
2017

25. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Author

Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, JB, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, XZ, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, and Kwiatkowski, DP

Subjects
Genotype, 030231 tropical medicine, Population, Plasmodium falciparum, Genomics, Biology, Polymorphism, Single Nucleotide, Deep sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Humans, Genetic variability, Malaria, Falciparum, education, Genotyping, Alleles, Phylogeny, 030304 developmental biology, Genetics, Whole genome sequencing, 0303 health sciences, Genetic diversity, education.field_of_study, Principal Component Analysis, Multidisciplinary, High-Throughput Nucleotide Sequencing, Biodiversity, biology.organism_classification, 3. Good health, Genome, Protozoan
Abstract

methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genomewide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome. The genetic diversity and evolutionary plasticity of P. falciparum are major obstacles for malaria elimination. New forms of resistance against antimalarial drugs are continually emerging 1,2 , and new forms of antigenic variation are a critical point of vulnerability for future malaria vaccines. Effective tools are needed to detect evolutionary changes in the parasite population and to monitor the spread of genetic variants that affect malaria control. Here we describe the use of deep sequencing to analyse P. falciparum diversity, using blood samples from patients with malaria. The P. falciparum genome has several unusual features that greatly complicate sequence analysis, such as extreme AT bias, large tracts of nonunique sequence and several large families of intensely polymorphic genes 3 . Our aim was therefore not to determine the entire genome sequence of individual field samples—which would be prohibitively expensive with current technologies—but to define an initial set of single nucleotide polymorphisms (SNPs) distributed across the P. falciparum genome, whose genotype can be ascertained with confidence in parasitized blood samples by deep sequencing. An additional complication in the analysis of P. falciparum genome variation is that the billions of haploid parasites that infect a single individual can be a complex mixture of genetic types. Previous studies 4–8 have largely focused on laboratory-adapted parasite clones, but the within-host diversity of natural infections is of fundamental biological interest. Parasites in the blood replicate asexually, but when they are taken up in the blood meal of an Anopheles mosquito they undergo sexual mating. If the parasites in the blood are of diverse genetic types, this process of sexual mating can generate novel recombinant forms. Deep sequencing provides new ways of investigating within-host diversity and the role of sexual recombination in parasite evolution.

Published
2016

26. Modulation of Aneuploidy in Leishmania donovani during Adaptation to Different In Vitro and In Vivo Environments and Its Impact on Gene Expression

Author

Dumetz, F., primary, Imamura, H., additional, Sanders, M., additional, Seblova, V., additional, Myskova, J., additional, Pescher, P., additional, Vanaerschot, M., additional, Meehan, C. J., additional, Cuypers, B., additional, De Muylder, G., additional, Späth, G. F., additional, Bussotti, G., additional, Vermeesch, J. R., additional, Berriman, M., additional, Cotton, J. A., additional, Volf, P., additional, Dujardin, J. C., additional, and Domagalska, M. A., additional

Published
2017
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27. Global Gene Expression Profiling through the Complete Life Cycle of Trypanosoma vivax

Author

Jackson, AP, Goyard, S, Xia, D, Foth, BJ, Sanders, M, Wastling, JM, Minoprio, P, and Berriman, M

Subjects
Life Cycle Stages, lcsh:Arctic medicine. Tropical medicine, Species Specificity, lcsh:RC955-962, lcsh:Public aspects of medicine, parasitic diseases, Protozoan Proteins, Gene Expression Regulation, Developmental, lcsh:RA1-1270, Trypanosoma vivax, Transcriptome, QR, Research Article
Abstract

The parasitic flagellate Trypanosoma vivax is a cause of animal trypanosomiasis across Africa and South America. The parasite has a digenetic life cycle, passing between mammalian hosts and insect vectors, and a series of developmental forms adapted to each life cycle stage. Each point in the life cycle presents radically different challenges to parasite metabolism and physiology and distinct host interactions requiring remodeling of the parasite cell surface. Transcriptomic and proteomic studies of the related parasites T. brucei and T. congolense have shown how gene expression is regulated during their development. New methods for in vitro culture of the T. vivax insect stages have allowed us to describe global gene expression throughout the complete T. vivax life cycle for the first time. We combined transcriptomic and proteomic analysis of each life stage using RNA-seq and mass spectrometry respectively, to identify genes with patterns of preferential transcription or expression. While T. vivax conforms to a pattern of highly conserved gene expression found in other African trypanosomes, (e.g. developmental regulation of energy metabolism, restricted expression of a dominant variant antigen, and expression of ‘Fam50’ proteins in the insect mouthparts), we identified significant differences in gene expression affecting metabolism in the fly and a suite of T. vivax-specific genes with predicted cell-surface expression that are preferentially expressed in the mammal (‘Fam29, 30, 42’) or the vector (‘Fam34, 35, 43’). T. vivax differs significantly from other African trypanosomes in the developmentally-regulated proteins likely to be expressed on its cell surface and thus, in the structure of the host-parasite interface. These unique features may yet explain the species differences in life cycle and could, in the form of bloodstream-stage proteins that do not undergo antigenic variation, provide targets for therapy., Author Summary Trypanosoma vivax is a single-celled parasite that infects cattle and non-domesticated animals through the bite of the tsetse fly. The parasite causes animal trypanosomiasis, a chronic condition resulting in severe anemia, muscle wastage and ultimately death if untreated. This disease is endemic across sub-Saharan Africa but has also spread to South America and causes considerable losses in animal productivity, impeding economic development in the world’s poorest nations. To develop new ways of preventing and treating animal trypanosomiasis, we need an accurate understanding of how the parasite causes disease. In this study, we present an analysis of gene expression throughout the T. vivax life cycle that compares the abundance of gene transcripts (mRNA) and proteins in the mammalian and insect hosts. We have identified genes that are preferentially expressed in each life stage, including many that are unique to T. vivax and probably expressed on its cell surface. Our findings provide a comprehensive understanding of how gene expression is regulated in T. vivax and further refine a pool of T. vivax-specific genes that could be exploited to prevent and treat animal trypanosomiasis.

Published
2015

30. Phosphoinositide Metabolism Links cGMP- Dependent Protein Kinase G to Essential Ca (2+) Signals at Key Decision Points in the Life Cycle of Malaria Parasites

Author

Brochet, M., Collins, M.O., Smith, T.K., Thompson, E., Sebastian, S., Volkmann, K., Schwach, F., Chappell, L., Gomes, A.R., Berriman, M., Rayner, J.C., Baker, D.A., Choudhary, J., and Billker, O.

Subjects
parasitic diseases, cardiovascular system
Abstract

Many critical events in the Plasmodium life cycle rely on the controlled release of Ca2+ from intracellular stores to activate stage-specific Ca2+-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca2+ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca2+ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5)-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca2+ effectors, PKG emerges as a unifying factor to control multiple cellular Ca2+ signals essential for malaria parasite development and transmission.

Published
2014

31. Genome sequence of the tsetse fly (Glossina morsitans) : vector of African trypanosomiasis

Author

Watanabe, J., Hattori, M., Berriman, M., Lehane, M. J., Hall, N., Solano, Philippe, Aksoy, S., Hide, W., Toure, Y., Attardo, G. M., Darby, A. C., Toyoda, A., Hertz-Fowler, C., Larkin, D. M., Cotton, J. A., Sanders, M. J., Swain, M. T., Quail, M. A., Inoue, N., and Ravel, Sophie

Abstract

Tsetse flies are the sole vectors of human African trypanosomiasis throughout sub-Saharan Africa. Both sexes of adult tsetse feed exclusively on blood and contribute to disease transmission. Notable differences between tsetse and other disease vectors include obligate microbial symbioses, viviparous reproduction, and lactation. Here, we describe the sequence and annotation of the 366-megabase Glossina morsitans morsitans genome. Analysis of the genome and the 12,308 predicted protein-encoding genes led to multiple discoveries, including chromosomal integrations of bacterial (Wolbachia) genome sequences, a family of lactation-specific proteins, reduced complement of host pathogen recognition proteins, and reduced olfaction/ chemosensory associated genes. These genome data provide a foundation for research into trypanosomiasis prevention and yield important insights with broad implications for multiple aspects of tsetse biology.

Published
2014

32. TrypanoCyc: A community-led biochemical pathways database for Trypanosoma brucei

Author

Shameer, S. (Sanu), Logan-Klumpler, F.J. (Flora J.), Vinson, F. (Florence), Cottret, L. (Ludovic), Merlet, B. (Benjamin), Achcar, F. (Fiona), Boshart, M. (Michael), Berriman, M. (Matthew), Breitling, R. (Rainer), Bringaud, F. (Frédéric), Bütikofer, P. (Peter), Cattanach, A.M. (Amy M.), Bannerman-Chukualim, B. (Bridget), Creek, D.J. (Darren J.), Crouch, K. (Kathryn), De Koning, H.P. (Harry P.), Denise, H. (Hubert), Ebikeme, C. (Charles), Fairlamb, A.H. (Alan H.), Ferguson, M.A.J. (Michael A. J.), Ginger, M.L. (Michael L.), Hertz-Fowler, C. (Christiane), Kerkhoven, E.J. (Eduard), Mäser, P. (Pascal), Michels, P.A.M. (Paul), Nayak, A. (Archana), Nes, D. (DavidW.), Nolan, D.P. (Derek P.), Olsen, C. (Christian), Silva-Franco, F. (Fatima), Smith, T.K. (Terry K.), Taylor, M.C. (Martin C.), Tielens, A.G.M. (Lodewijk), Urbaniak, M.D. (Michael D.), Hellemond, J.J. (Jaap) van, Vincent, I.M. (Isabel M.), Wilkinson, S.R. (Shane R.), Wyllie, S. (Susan), Opperdoes, F.R. (Fred), Barrett, M.P. (Michael P.), Jourdan, F. (Fabien), Shameer, S. (Sanu), Logan-Klumpler, F.J. (Flora J.), Vinson, F. (Florence), Cottret, L. (Ludovic), Merlet, B. (Benjamin), Achcar, F. (Fiona), Boshart, M. (Michael), Berriman, M. (Matthew), Breitling, R. (Rainer), Bringaud, F. (Frédéric), Bütikofer, P. (Peter), Cattanach, A.M. (Amy M.), Bannerman-Chukualim, B. (Bridget), Creek, D.J. (Darren J.), Crouch, K. (Kathryn), De Koning, H.P. (Harry P.), Denise, H. (Hubert), Ebikeme, C. (Charles), Fairlamb, A.H. (Alan H.), Ferguson, M.A.J. (Michael A. J.), Ginger, M.L. (Michael L.), Hertz-Fowler, C. (Christiane), Kerkhoven, E.J. (Eduard), Mäser, P. (Pascal), Michels, P.A.M. (Paul), Nayak, A. (Archana), Nes, D. (DavidW.), Nolan, D.P. (Derek P.), Olsen, C. (Christian), Silva-Franco, F. (Fatima), Smith, T.K. (Terry K.), Taylor, M.C. (Martin C.), Tielens, A.G.M. (Lodewijk), Urbaniak, M.D. (Michael D.), Hellemond, J.J. (Jaap) van, Vincent, I.M. (Isabel M.), Wilkinson, S.R. (Shane R.), Wyllie, S. (Susan), Opperdoes, F.R. (Fred), Barrett, M.P. (Michael P.), and Jourdan, F. (Fabien)

Abstract

The metabolic network of a cell represents the catabolic and anabolic reactions that interconvert small molecules (metabolites) through the activity of enzymes, transporters and non-catalyzed chemical reactions. Our understanding of individualmetabolic networks is increasing as we learn more about the enzymes that are active in particular cells under particular conditions and as technologies advance to allow detailed measurements of the cellular metabolome. Metabolic network databases are of increasing importance in allowing us to contextualise data sets emerging from transcriptomic, proteomic and metabolomic experiments. Here we present a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describes the generic and condition-specific metabolic network of Trypanosoma brucei, a parasitic protozoan responsible for human and animal African trypanosomiasis. In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have also implemented a network-based representation of the information through MetExplore, yielding a novel environment in which to visualise the metabolism of this important parasite.

Published
2015
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33. TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei

Author

Shameer, S, Logan-Klumpler, FJ, Vinson, F, Cottret, L, Merlet, B, Achcar, F, Boshart, M, Berriman, M, Breitling, R, Bringaud, F, Butikofer, P, Cattanach, AM, Bannerman-Chukualim, B, Creek, DJ, Crouch, K, de Koning, HP, Denise, H, Ebikeme, C, Fairlamb, AH, Ferguson, MAJ, Ginger, ML, Hertz-Fowler, C, Kerkhoven, EJ, Maeser, P, Michels, PAM, Nayak, A, Nes, DW, Nolan, DP, Olsen, C, Silva-Franco, F, Smith, TK, Taylor, MC, Tielens, AGM, Urbaniak, MD, van Hellemond, JJ, Vincent, IM, Wilkinson, SR, Wyllie, S, Opperdoes, FR, Barrett, MP, Jourdan, F, Shameer, S, Logan-Klumpler, FJ, Vinson, F, Cottret, L, Merlet, B, Achcar, F, Boshart, M, Berriman, M, Breitling, R, Bringaud, F, Butikofer, P, Cattanach, AM, Bannerman-Chukualim, B, Creek, DJ, Crouch, K, de Koning, HP, Denise, H, Ebikeme, C, Fairlamb, AH, Ferguson, MAJ, Ginger, ML, Hertz-Fowler, C, Kerkhoven, EJ, Maeser, P, Michels, PAM, Nayak, A, Nes, DW, Nolan, DP, Olsen, C, Silva-Franco, F, Smith, TK, Taylor, MC, Tielens, AGM, Urbaniak, MD, van Hellemond, JJ, Vincent, IM, Wilkinson, SR, Wyllie, S, Opperdoes, FR, Barrett, MP, and Jourdan, F

Abstract

The metabolic network of a cell represents the catabolic and anabolic reactions that interconvert small molecules (metabolites) through the activity of enzymes, transporters and non-catalyzed chemical reactions. Our understanding of individual metabolic networks is increasing as we learn more about the enzymes that are active in particular cells under particular conditions and as technologies advance to allow detailed measurements of the cellular metabolome. Metabolic network databases are of increasing importance in allowing us to contextualise data sets emerging from transcriptomic, proteomic and metabolomic experiments. Here we present a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describes the generic and condition-specific metabolic network of Trypanosoma brucei, a parasitic protozoan responsible for human and animal African trypanosomiasis. In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have also implemented a network-based representation of the information through MetExplore, yielding a novel environment in which to visualise the metabolism of this important parasite.

Published
2015

34. Differences between Trypanosoma brucei gambiense groups 1 and 2 in their resistance to killing by Trypanolytic factor 1

Author

Capewell, P., Veitch, N.J., Turner, C.M.R., Raper, J., Berriman, M., Hajduk, S.L., and MacLeod, A.

Abstract

Background: The three sub-species of Trypanosoma brucei are important pathogens of sub-Saharan Africa. T. b. brucei is unable to infect humans due to sensitivity to trypanosome lytic factors (TLF) 1 and 2 found in human serum. T. b. rhodesiense and T. b. gambiense are able to resist lysis by TLF. There are two distinct sub-groups of T. b. gambiense that differ genetically and by human serum resistance phenotypes. Group 1 T. b. gambiense have an invariant phenotype whereas group 2 show variable resistance. Previous data indicated that group 1 T. b. gambiense are resistant to TLF-1 due in-part to reduced uptake of TLF-1 mediated by reduced expression of the TLF-1 receptor (the haptoglobin-hemoglobin receptor (HpHbR)) gene. Here we investigate if this is also true in group 2 parasites. \ud \ud Methodology: Isogenic resistant and sensitive group 2 T. b. gambiense were derived and compared to other T. brucei parasites. Both resistant and sensitive lines express the HpHbR gene at similar levels and internalized fluorescently labeled TLF-1 similar fashion to T. b. brucei. Both resistant and sensitive group 2, as well as group 1 T. b. gambiense, internalize recombinant APOL1, but only sensitive group 2 parasites are lysed. \ud \ud Conclusions: Our data indicate that, despite group 1 T. b. gambiense avoiding TLF-1, it is resistant to the main lytic component, APOL1. Similarly group 2 T. b. gambiense is innately resistant to APOL1, which could be based on the same mechanism. However, group 2 T. b. gambiense variably displays this phenotype and expression does not appear to correlate with a change in expression site or expression of HpHbR. Thus there are differences in the mechanism of human serum resistance between T. b. gambiense groups 1 and 2.

Published
2011

35. The genome sequence of Trypanosoma brucei gambiense, causative agent of chronic Human African Trypanosomiasis

Author

Jackson, A., Sanders, M., Berry, A., McQuillan, J., Aslett, M., Quail, M.A., Chukualim, B., Capewell, P., MacLeod, A., Melville, S., Gibson, W., Barry, J.D., Berriman, M., and Hertz-Fowler, C.

Abstract

Background: Trypanosoma brucei gambiense is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a T. b. brucei isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between T. b. gambiense and the reference genome. We sought to identify features that were uniquely associated with T. b. gambiense and its ability to infect humans.\ud \ud Methods and findings: An improved high-quality draft genome sequence for the group 1 T. b. gambiense DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with T. b. brucei showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in T. b. gambiense DAL 972. A comparison of the variant surface glycoproteins (VSG) in T. b. brucei with all T. b. gambiense sequence reads showed that the essential structural repertoire of VSG domains is conserved across T. brucei.\ud \ud Conclusions: This study provides the first estimate of intraspecific genomic variation within T. brucei, and so has important consequences for future population genomics studies. We have shown that the T. b. gambiense genome corresponds closely with the reference, which should therefore be an effective scaffold for any T. brucei genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in T. b. brucei, no T. b. gambiense-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans.

Published
2010

36. A comprehensive evaluation of rodent malaria parasite genomes and gene expression

Author

Otto, T.D., Bohme, U., Jackson, A.P., Hunt, M., Franke-Fayard, B., Hoeijmakers, W.A.M., Religa, A.A., Robertson, L., Sanders, M., Ogun, S.A., Cunningham, D., Erhart, A., Billker, O., Khan, S.M., Stunnenberg, H.G., Langhorne, J., Holder, A.A., Waters, A.P., Newbold, C.I., Pain, A., Berriman, M., Janse, C.J., Otto, T.D., Bohme, U., Jackson, A.P., Hunt, M., Franke-Fayard, B., Hoeijmakers, W.A.M., Religa, A.A., Robertson, L., Sanders, M., Ogun, S.A., Cunningham, D., Erhart, A., Billker, O., Khan, S.M., Stunnenberg, H.G., Langhorne, J., Holder, A.A., Waters, A.P., Newbold, C.I., Pain, A., Berriman, M., and Janse, C.J.

Abstract

Contains fulltext : 133083.pdf (publisher's version ) (Open Access)

Published
2014

37. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

Author

Vaidya, AB, Morrisey, JM, Zhang, Z, Das, S, Daly, TM, Otto, TD, Spillman, NJ, Wyvratt, M, Siegl, P, Marfurt, J, Wirjanata, G, Sebayang, BF, Price, RN, Chatterjee, A, Nagle, A, Stasiak, M, Charman, SA, Angulo-Barturen, I, Ferrer, S, Belen Jimenez-Diaz, M, Santos Martinez, M, Javier Gamo, F, Avery, VM, Ruecker, A, Delves, M, Kirk, K, Berriman, M, Kortagere, S, Burrows, J, Fan, E, Bergman, LW, Vaidya, AB, Morrisey, JM, Zhang, Z, Das, S, Daly, TM, Otto, TD, Spillman, NJ, Wyvratt, M, Siegl, P, Marfurt, J, Wirjanata, G, Sebayang, BF, Price, RN, Chatterjee, A, Nagle, A, Stasiak, M, Charman, SA, Angulo-Barturen, I, Ferrer, S, Belen Jimenez-Diaz, M, Santos Martinez, M, Javier Gamo, F, Avery, VM, Ruecker, A, Delves, M, Kirk, K, Berriman, M, Kortagere, S, Burrows, J, Fan, E, and Bergman, LW

Abstract

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

Published
2014

38. Differential PfEMP1 Expression Is Associated with Cerebral Malaria Pathology

Author

Smith, J, Tembo, DL, Nyoni, B, Murikoli, RV, Mukaka, M, Milner, DA, Berriman, M, Rogerson, SJ, Taylor, TE, Molyneux, ME, Mandala, WL, Craig, AG, Montgomery, J, Smith, J, Tembo, DL, Nyoni, B, Murikoli, RV, Mukaka, M, Milner, DA, Berriman, M, Rogerson, SJ, Taylor, TE, Molyneux, ME, Mandala, WL, Craig, AG, and Montgomery, J

Abstract

Plasmodium falciparum is unique among human malarias in its ability to sequester in post-capillary venules of host organs. The main variant antigens implicated are the P. falciparum erythrocyte membrane protein 1 (PfEMP1), which can be divided into three major groups (A-C). Our study was a unique examination of sequestered populations of parasites for genetic background and expression of PfEMP1 groups. We collected post-mortem tissue from twenty paediatric hosts with pathologically different forms of cerebral malaria (CM1 and CM2) and parasitaemic controls (PC) to directly examine sequestered populations of parasites in the brain, heart and gut. Use of two different techniques to investigate this question produced divergent results. By quantitative PCR, group A var genes were upregulated in all three organs of CM2 and PC cases. In contrast, in CM1 infections displaying high levels of sequestration but negligible vascular pathology, there was high expression of group B var. Cloning and sequencing of var transcript tags from the same samples indicated a uniformly low expression of group A-like var. Generally, within an organ sample, 1-2 sequences were expressed at dominant levels. 23% of var tags were detected in multiple patients despite the P. falciparum infections being genetically distinct, and two tags were observed in up to seven hosts each with high expression in the brains of 3-4 patients. This study is a novel examination of the sequestered parasites responsible for fatal cerebral malaria and describes expression patterns of the major cytoadherence ligand in three organ-derived populations and three pathological states.

Published
2014

40. The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host-parasite interaction

Author

Jackson, A. P., primary, Otto, T. D., additional, Darby, A., additional, Ramaprasad, A., additional, Xia, D., additional, Echaide, I. E., additional, Farber, M., additional, Gahlot, S., additional, Gamble, J., additional, Gupta, D., additional, Gupta, Y., additional, Jackson, L., additional, Malandrin, L., additional, Malas, T. B., additional, Moussa, E., additional, Nair, M., additional, Reid, A. J., additional, Sanders, M., additional, Sharma, J., additional, Tracey, A., additional, Quail, M. A., additional, Weir, W., additional, Wastling, J. M., additional, Hall, N., additional, Willadsen, P., additional, Lingelbach, K., additional, Shiels, B., additional, Tait, A., additional, Berriman, M., additional, Allred, D. R., additional, and Pain, A., additional

Published
2014
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41. SchistoDB: an updated genome resource for the three key schistosomes of humans

Author

Zerlotini, A, Aguiar, ERGR, Yu, F, Xu, H, Li, Y, Young, ND, Gasser, RB, Protasio, AV, Berriman, M, Roos, DS, Kissinger, JC, Oliveira, G, Zerlotini, A, Aguiar, ERGR, Yu, F, Xu, H, Li, Y, Young, ND, Gasser, RB, Protasio, AV, Berriman, M, Roos, DS, Kissinger, JC, and Oliveira, G

Abstract

The new release of SchistoDB (http://SchistoDB.net) provides a rich resource of genomic data for key blood flukes (genus Schistosoma) which cause disease in hundreds of millions of people worldwide. SchistoDB integrates whole-genome sequence and annotation of three species of the genus and provides enhanced bioinformatics analyses and data-mining tools. A simple, yet comprehensive web interface provided through the Strategies Web Development Kit is available for the mining and visualization of the data. Genomic scale data can be queried based on BLAST searches, annotation keywords and gene ID searches, gene ontology terms, sequence motifs, protein characteristics and phylogenetic relationships. Search strategies can be saved within a user's profile for future retrieval and may also be shared with other researchers using a unique web address.

Published
2013

42. The genomes of four tapeworm species reveal adaptations to parasitism

Author

Tsai, I J, Zarowiecki, M, Holroyd, N, Garciarrubio, A, Sanchez-Flores, A, Brooks, K L, Tracey, A, Bobes, R J, Fragos, G, Sciutto, E, Aslett, M, Beasley, H, Bennett, H M, Cai, J, Camicia, F, Clark, R, Cucher, M, De Silva, N, Day, T A, Deplazes, P, Estrada, K, Fernández, C, Holland, P W, Hou, J, Hu, S, Huckvale, T, Hung, S S, Kamenetzky, L, Keane, J A, Kiss, F, Koziol, U, Lambert, O, Liu, K, Luo, X, Luo, Y, Macchiaroli, N, Nichol, S, Paps, J, Parkinson, J, Pouchkina-Stantcheva, N, Riddiford, N, Rosenzvit, M, Salinas, G, Wasmuth, J D, Zamanian, M, Zheng, Y, Fragoso, G, Sánchez-Flores, A, Cevallos, M A, Morett, E, González, V, Portillo, T, Ochoa-Leyva, A, José, M V, Landa, A, Jiménez, L, Valdés, V, Carrero, J C, Larralde, C, Morales-Montor, J, Limón-Lason, J, Soberón, X, Laclette, J P, Cai, X, Olson, P D, Brehm, K, Berriman, M, Tsai, I J, Zarowiecki, M, Holroyd, N, Garciarrubio, A, Sanchez-Flores, A, Brooks, K L, Tracey, A, Bobes, R J, Fragos, G, Sciutto, E, Aslett, M, Beasley, H, Bennett, H M, Cai, J, Camicia, F, Clark, R, Cucher, M, De Silva, N, Day, T A, Deplazes, P, Estrada, K, Fernández, C, Holland, P W, Hou, J, Hu, S, Huckvale, T, Hung, S S, Kamenetzky, L, Keane, J A, Kiss, F, Koziol, U, Lambert, O, Liu, K, Luo, X, Luo, Y, Macchiaroli, N, Nichol, S, Paps, J, Parkinson, J, Pouchkina-Stantcheva, N, Riddiford, N, Rosenzvit, M, Salinas, G, Wasmuth, J D, Zamanian, M, Zheng, Y, Fragoso, G, Sánchez-Flores, A, Cevallos, M A, Morett, E, González, V, Portillo, T, Ochoa-Leyva, A, José, M V, Landa, A, Jiménez, L, Valdés, V, Carrero, J C, Larralde, C, Morales-Montor, J, Limón-Lason, J, Soberón, X, Laclette, J P, Cai, X, Olson, P D, Brehm, K, and Berriman, M

Abstract

Tapeworms (Cestoda) cause neglected diseases that can be fatal and are difficult to treat, owing to inefficient drugs. Here we present an analysis of tapeworm genome sequences using the human-infective species Echinococcus multilocularis, E. granulosus, Taenia solium and the laboratory model Hymenolepis microstoma as examples. The 115- to 141-megabase genomes offer insights into the evolution of parasitism. Synteny is maintained with distantly related blood flukes but we find extreme losses of genes and pathways that are ubiquitous in other animals, including 34 homeobox families and several determinants of stem cell fate. Tapeworms have specialized detoxification pathways, metabolism that is finely tuned to rely on nutrients scavenged from their hosts, and species-specific expansions of non-canonical heat shock proteins and families of known antigens. We identify new potential drug targets, including some on which existing pharmaceuticals may act. The genomes provide a rich resource to underpin the development of urgently needed treatments and control.

Published
2013

43. Schistosoma mansoni (Blood Fluke) Sulfotransferase

Author

Valentim, C.L.L., primary, Cioli, D., additional, Chevalier, F.D., additional, Cao, X., additional, Taylor, A.B., additional, Holloway, S.P., additional, Pica-Mattoccia, L., additional, Guidi, A., additional, Basso, A., additional, Tsai, I.J., additional, Berriman, M., additional, Carvalho-Queiroz, C., additional, Almeida, M., additional, Aguilar, H., additional, Frantz, D.E., additional, Hart, P.J., additional, Anderson, T.J.C., additional, and LoVerde, P.T., additional

Published
2013
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44. Schistosoma mansoni (Blood Fluke) Sulfotransferase/Oxamniquine Complex

Author

Valentim, C.L.L., primary, Cioli, D., additional, Chevalier, F.D., additional, Cao, X., additional, Taylor, A.B., additional, Holloway, S.P., additional, Pica-Mattoccia, L., additional, Guidi, A., additional, Basso, A., additional, Tsai, I.J., additional, Berriman, M., additional, Carvalho-Queiroz, C., additional, Almeida, M., additional, Aguilar, H., additional, Frantz, D.E., additional, Hart, P.J., additional, Anderson, T.J.C., additional, and LoVerde, P.T., additional

Published
2013
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46. Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites

Author

Valentim, C. L. L., primary, Cioli, D., additional, Chevalier, F. D., additional, Cao, X., additional, Taylor, A. B., additional, Holloway, S. P., additional, Pica-Mattoccia, L., additional, Guidi, A., additional, Basso, A., additional, Tsai, I. J., additional, Berriman, M., additional, Carvalho-Queiroz, C., additional, Almeida, M., additional, Aguilar, H., additional, Frantz, D. E., additional, Hart, P. J., additional, LoVerde, P. T., additional, and Anderson, T. J. C., additional

Published
2013
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47. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Author

Manske, Magnus, Miotto, Olivo, Campino, Susana, Auburn, Sarah, Almagro-Gracia, J, Maslen, Gareth, O'Brien, J, Djimde, Abdoulaye, Doumbo, Ogobara, Zongo, Issaka, Ouedraogo, Jean, Michon, Pascal, Mueller, Ivo, Siba, Peter, Nzila, Alexis, Borrman, Steffen, Kiara, Steven, Marsh, Kevin, Jiang, Hongying, Su, Xin-Zhuan, Amaratunga, Chanaki, Fairhurst, Rick, Socheat, Duong, Nosten, François, Imwong, Mallika, White, Nicholas J, Sanders, Mandy, Anastasi, Elisa, Alcock, Daniel, Drury, Eleanor, Oyola, S, Quail, Michael, Turner, Daniel, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, Kate, Sutherland, Colin, Roper, C, Mangano, Valentina, Modiano, d, Tan, J, Ferdig, M, Amambua-Ngwa, A, Conway, D, Takala-Harrison, S, Plowe, C, Rayner, J, Rockett, Kirk, Clark, Taane, Newbold, Christopher, Berriman, M, MacInnis, Bronwyn, Kwiatkowski, Dominic, Manske, Magnus, Miotto, Olivo, Campino, Susana, Auburn, Sarah, Almagro-Gracia, J, Maslen, Gareth, O'Brien, J, Djimde, Abdoulaye, Doumbo, Ogobara, Zongo, Issaka, Ouedraogo, Jean, Michon, Pascal, Mueller, Ivo, Siba, Peter, Nzila, Alexis, Borrman, Steffen, Kiara, Steven, Marsh, Kevin, Jiang, Hongying, Su, Xin-Zhuan, Amaratunga, Chanaki, Fairhurst, Rick, Socheat, Duong, Nosten, François, Imwong, Mallika, White, Nicholas J, Sanders, Mandy, Anastasi, Elisa, Alcock, Daniel, Drury, Eleanor, Oyola, S, Quail, Michael, Turner, Daniel, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, Kate, Sutherland, Colin, Roper, C, Mangano, Valentina, Modiano, d, Tan, J, Ferdig, M, Amambua-Ngwa, A, Conway, D, Takala-Harrison, S, Plowe, C, Rayner, J, Rockett, Kirk, Clark, Taane, Newbold, Christopher, Berriman, M, MacInnis, Bronwyn, and Kwiatkowski, Dominic

Published
2012

48. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Author

Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, J-B, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, X-Z, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, Kwiatkowski, DP, Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, J-B, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, X-Z, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, and Kwiatkowski, DP

Abstract

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

Published
2012

49. A deep sequencing approach to comparatively analyze the transcriptome of lifecycle stages of the filarial worm, brugia malayi

Author

Choi, YJ, Ghedin, E, Berriman, M, McQuillan, J, Holroyd, N, Mayhew, GF, Christensen, BM, Michalski, ML, Choi, YJ, Ghedin, E, Berriman, M, McQuillan, J, Holroyd, N, Mayhew, GF, Christensen, BM, and Michalski, ML

Abstract

Background: Developing intervention strategies for the control of parasitic nematodes continues to be a significant challenge. Genomic and post-genomic approaches play an increasingly important role for providing fundamental molecular information about these parasites, thus enhancing basic as well as translational research. Here we report a comprehensive genome-wide survey of the developmental transcriptome of the human filarial parasite Brugia malayi. Methodology/Principal Findings: Using deep sequencing, we profiled the transcriptome of eggs and embryos, immature (≤3 days of age) and mature microfilariae (MF), third- and fourth-stage larvae (L3 and L4), and adult male and female worms. Comparative analysis across these stages provided a detailed overview of the molecular repertoires that define and differentiate distinct lifecycle stages of the parasite. Genome-wide assessment of the overall transcriptional variability indicated that the cuticle collagen family and those implicated in molting exhibit noticeably dynamic stage-dependent patterns. Of particular interest was the identification of genes displaying sex-biased or germline-enriched profiles due to their potential involvement in reproductive processes. The study also revealed discrete transcriptional changes during larval development, namely those accompanying the maturation of MF and the L3 to L4 transition that are vital in establishing successful infection in mosquito vectors and vertebrate hosts, respectively. Conclusions/Significance: Characterization of the transcriptional program of the parasite's lifecycle is an important step toward understanding the developmental processes required for the infectious cycle. We find that the transcriptional program has a number of stage-specific pathways activated during worm development. In addition to advancing our understanding of transcriptome dynamics, these data will aid in the study of genome structure and organization by facilitating the identification of

Published
2011

50. Identification of Attractive Drug Targets in Neglected-Disease Pathogens Using an In Silico Approach

Author

Dalton, JP, Crowther, GJ, Shanmugam, D, Carmona, SJ, Doyle, MA, Hertz-Fowler, C, Berriman, M, Nwaka, S, Ralph, SA, Roos, DS, Van Voorhis, WC, Agueero, F, Dalton, JP, Crowther, GJ, Shanmugam, D, Carmona, SJ, Doyle, MA, Hertz-Fowler, C, Berriman, M, Nwaka, S, Ralph, SA, Roos, DS, Van Voorhis, WC, and Agueero, F

Abstract

BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates

Published
2010

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