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Relph, Katharine A.; Russell, Clark D.; Fairfield, Cameron J.; Turtle, Lance, de Silva, Thushan I.; Siggins, Matthew K.; Drake, Thomas M.; Thwaites, Ryan S.; Abrams, Simon, Moore, Shona C.; Hardwick, Hayley E.; Oosthuyzen, Wilna, Harrison, Ewen M.; Docherty, Annemarie B.; Openshaw, Peter J. M.; Baillie, J. Kenneth, Semple, Malcolm G.; Ho, Antonia, Baillie, J. Kenneth, Semple, Malcolm G.; Openshaw, Peter J. M.; Carson, Gail, Alex, Beatrice, Bach, Benjamin, Barclay, Wendy S.; Bogaert, Debby, Chand, Meera, Cooke, Graham S.; Docherty, Annemarie B.; Dunning, Jake, Filipe, Ana da Silva, Fletcher, Tom, Green, Christopher A.; Harrison, Ewen M.; Hiscox, Julian A.; Ho, Antonia Ying Wai, Horby, Peter W.; Ijaz, Samreen, Khoo, Saye, Klenerman, Paul, Law, Andrew, Lim, Wei Shen, Mentzer, Alexander J.; Merson, Laura, Meynert, Alison M.; Noursadeghi, Mahdad, Moore, Shona C.; Palmarini, Massimo, Paxton, William A.; Pollakis, Georgios, Price, Nicholas, Rambaut, Andrew, Robertson, David L.; Russell, Clark D.; Sancho-Shimizu, Vanessa, Scott, Janet T.; de Silva, Thushan, Sigfrid, Louise, Solomon, Tom, Sriskandan, Shiranee, Stuart, David, Summers, Charlotte, Tedder, Richard S.; Thomson, Emma C.; Roger Thompson, A. A.; Thwaites, Ryan S.; Turtle, Lance C. W.; Gupta, Rishi K.; Zambon, Maria, Hardwick, Hayley, Donohue, Chloe, Lyons, Ruth, Griffiths, Fiona, Oosthuyzen, Wilna, Norman, Lisa, Pius, Riinu, Drake, Thomas M.; Fairfield, Cameron J.; Knight, Stephen R.; McLean, Kenneth A.; Murphy, Derek, Shaw, Catherine A.; Dalton, Jo, Girvan, Michelle, Saviciute, Egle, Roberts, Stephanie, Harrison, Janet, Marsh, Laura, Connor, Marie, Halpin, Sophie, Jackson, Clare, Gamble, Carrol, Leeming, Gary, Law, Andrew, Wham, Murray, Clohisey, Sara, Hendry, Ross, Scott-Brown, James, Greenhalf, William, Shaw, Victoria, McDonald, Sara, Keating, Seán, Ahmed, Katie A.; Armstrong, Jane A.; Ashworth, Milton, Asiimwe, Innocent G.; Bakshi, Siddharth, Barlow, Samantha L.; Booth, Laura, Brennan, Benjamin, Bullock, Katie, Catterall, Benjamin W. A.; Clark, Jordan J.; Clarke, Emily A.; Cole, Sarah, Cooper, Louise, Cox, Helen, Davis, Christopher, Dincarslan, Oslem, Dunn, Chris, Dyer, Philip, Elliott, Angela, Evans, Anthony, Finch, Lorna, Fisher, Lewis W. S.; Foster, Terry, Garcia-Dorival, Isabel, Greenhalf, William, Gunning, Philip, Hartley, Catherine, Jensen, Rebecca L.; Jones, Christopher B.; Jones, Trevor R.; Khandaker, Shadia, King, Katharine, Kiy, Robyn T.; Koukorava, Chrysa, Lake, Annette, Lant, Suzannah, Latawiec, Diane, Lavelle-Langham, Lara, Lefteri, Daniella, Lett, Lauren, Livoti, Lucia A.; Mancini, Maria, McDonald, Sarah, McEvoy, Laurence, McLauchlan, John, Metelmann, Soeren, Miah, Nahida S.; Middleton, Joanna, Mitchell, Joyce, Moore, Shona C.; Murphy, Ellen G.; Penrice-Randal, Rebekah, Pilgrim, Jack, Prince, Tessa, Reynolds, Will, Matthew Ridley, P.; Sales, Debby, Shaw, Victoria E.; Shears, Rebecca K.; Small, Benjamin, Subramaniam, Krishanthi S.; Szemiel, Agnieska, Taggart, Aislynn, Tanianis-Hughes, Jolanta, Thomas, Jordan, Trochu, Erwan, van Tonder, Libby, Wilcock, Eve, Eunice Zhang, J.; Flaherty, Lisa, Maziere, Nicole, Cass, Emily, Doce Carracedo, Alejandra, Carlucci, Nicola, Holmes, Anthony, Massey, Hannah, Murphy, Lee, Wrobel, Nicola, McCafferty, Sarah, Morrice, Kirstie, MacLean, Alan, Adeniji, Kayode, Agranoff, Daniel, Agwuh, Ken, Ail, Dhiraj, Aldera, Erin L.; Alegria, Ana, Angus, Brian, Ashish, Abdul, Atkinson, Dougal, Bari, Shahedal, Barlow, Gavin, Barnass, Stella, Barrett, Nicholas, Bassford, Christopher, Basude, Sneha, Baxter, David, Beadsworth, Michael, Bernatoniene, Jolanta, Berridge, John, Best, Nicola, Bothma, Pieter, Chadwick, David, Brittain-Long, Robin, Bulteel, Naomi, Burden, Tom, Burtenshaw, Andrew, Caruth, Vikki, Chadwick, David, Chambler, Duncan, Chee, Nigel, Child, Jenny, Chukkambotla, Srikanth, Clark, Tom, Collini, Paul, Cosgrove, Catherine, Cupitt, Jason, Cutino-Moguel, Maria-Teresa, Dark, Paul, Dawson, Chris, Dervisevic, Samir, Donnison, Phil, Douthwaite, Sam, DuRand, Ingrid, Dushianthan, Ahilanadan, Dyer, Tristan, Evans, Cariad, Eziefula, Chi, Fegan, Christopher, Finn, Adam, Fullerton, Duncan, Garg, Sanjeev, Garg, Sanjeev, Garg, Atul, Gkrania-Klotsas, Effrossyni, Godden, Jo, Goldsmith, Arthur, Graham, Clive, Hardy, Elaine, Hartshorn, Stuart, Harvey, Daniel, Havalda, Peter, Hawcutt, Daniel B.; Hobrok, Maria, Hodgson, Luke, Hormis, Anil, Jacobs, Michael, Jain, Susan, Jennings, Paul, Kaliappan, Agilan, Kasipandian, Vidya, Kegg, Stephen, Kelsey, Michael, Kendall, Jason, Kerrison, Caroline, Kerslake, Ian, Koch, Oliver, Koduri, Gouri, Koshy, George, Laha, Shondipon, Laird, Steven, Larkin, Susan, Leiner, Tamas, Lillie, Patrick, Limb, James, Linnett, Vanessa, Little, Jeff, Lyttle, Mark, MacMahon, Michael, MacNaughton, Emily, Mankregod, Ravish, Masson, Huw, Matovu, Elijah, McCullough, Katherine, McEwen, Ruth, Meda, Manjula, Mills, Gary, Minton, Jane, Mirfenderesky, Mariyam, Mohandas, Kavya, Mok, Quen, Moon, James, Moore, Elinoor, Morgan, Patrick, Morris, Craig, Mortimore, Katherine, Moses, Samuel, Mpenge, Mbiye, Mulla, Rohinton, Murphy, Michael, Nagel, Megan, Nagarajan, Thapas, Nelson, Mark, O’Shea, Matthew K.; Otahal, Igor, Ostermann, Marlies, Pais, Mark, Panchatsharam, Selva, Papakonstantinou, Danai, Paraiso, Hassan, Patel, Brij, Pattison, Natalie, Pepperell, Justin, Peters, Mark, Phull, Mandeep, Pintus, Stefania, Pooni, Jagtur Singh, Post, Frank, Price, David, Prout, Rachel, Rae, Nikolas, Reschreiter, Henrik, Reynolds, Tim, Richardson, Neil, Roberts, Mark, Roberts, Devender, Rose, Alistair, Rousseau, Guy, Ryan, Brendan, Saluja, Taranprit, Shah, Aarti, Shanmuga, Prad, Sharma, Anil, Shawcross, Anna, Sizer, Jeremy, Shankar-Hari, Manu, Smith, Richard, Snelson, Catherine, Spittle, Nick, Staines, Nikki, Stambach, Tom, Stewart, Richard, Subudhi, Pradeep, Szakmany, Tamas, Tatham, Kate, Thomas, Jo, Thompson, Chris, Thompson, Robert, Tridente, Ascanio, Tupper-Carey, Darell, Twagira, Mary, Ustianowski, Andrew, Vallotton, Nick, Vincent-Smith, Lisa, Visuvanathan, Shico, Vuylsteke, Alan, Waddy, Sam, Wake, Rachel, Walden, Andrew, Welters, Ingeborg, Whitehouse, Tony, Whittaker, Paul, Whittington, Ashley, Papineni, Padmasayee, Wijesinghe, Meme, Williams, Martin, Wilson, Lawrence, Cole, Sarah, Winchester, Stephen, Wiselka, Martin, Wolverson, Adam, Wootton, Daniel G.; Workman, Andrew, Yates, Bryan, Young, Peter.
Open Forum Infectious Diseases ; 9(5), 2022.
Article in English | PMC | ID: covidwho-1821760

ABSTRACT

Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).

2.
International Journal of Molecular Sciences ; 23(7):3448, 2022.
Article in English | MDPI | ID: covidwho-1762538

ABSTRACT

Microtubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians.

3.
Antiviral Res ; 194: 105167, 2021 10.
Article in English | MEDLINE | ID: covidwho-1370440

ABSTRACT

Niemann-Pick type C1 (NPC1) receptor is an endosomal membrane protein that regulates intracellular cholesterol traffic. This protein has been shown to play an important role for several viruses. It has been reported that SARS-CoV-2 enters the cell through plasma membrane fusion and/or endosomal entry upon availability of proteases. However, the whole process is not fully understood yet and additional viral/host factors might be required for viral fusion and subsequent viral replication. Here, we report a novel interaction between the SARS-CoV-2 nucleoprotein (N) and the cholesterol transporter NPC1. Furthermore, we have found that some compounds reported to interact with NPC1, carbazole SC816 and sulfides SC198 and SC073, were able to reduce SARS-CoV-2 viral infection with a good selectivity index in human cell infection models. These findings suggest the importance of NPC1 for SARS-CoV-2 viral infection and a new possible potential therapeutic target to fight against COVID-19.


Subject(s)
Biological Transport , COVID-19/drug therapy , Endosomes/virology , Niemann-Pick C1 Protein/analysis , SARS-CoV-2/physiology , Animals , Carbazoles/pharmacology , Chlorocebus aethiops , Endosomes/chemistry , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins , Membrane Fusion , Vero Cells , Virus Replication
4.
Nat Commun ; 12(1): 1260, 2021 02 24.
Article in English | MEDLINE | ID: covidwho-1101645

ABSTRACT

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.


Subject(s)
COVID-19/immunology , COVID-19/virology , Lung/pathology , Lung/virology , Animals , Disease Models, Animal , Female , Immunity, Cellular/physiology , Interferon-gamma/metabolism , Macaca fascicularis , Macaca mulatta , Male , Pandemics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
5.
Viruses ; 12(10)2020 10 14.
Article in English | MEDLINE | ID: covidwho-905965

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Sequencing the viral genome as the outbreak progresses is important, particularly in the identification of emerging isolates with different pathogenic potential and to identify whether nucleotide changes in the genome will impair clinical diagnostic tools such as real-time PCR assays. Although single nucleotide polymorphisms and point mutations occur during the replication of coronaviruses, one of the biggest drivers in genetic change is recombination. This can manifest itself in insertions and/or deletions in the viral genome. Therefore, sequencing strategies that underpin molecular epidemiology and inform virus biology in patients should take these factors into account. A long amplicon/read length-based RT-PCR sequencing approach focused on the Oxford Nanopore MinION/GridION platforms was developed to identify and sequence the SARS-CoV-2 genome in samples from patients with or suspected of COVID-19. The protocol, termed Rapid Sequencing Long Amplicons (RSLAs) used random primers to generate cDNA from RNA purified from a sample from a patient, followed by single or multiplex PCRs to generate longer amplicons of the viral genome. The base protocol was used to identify SARS-CoV-2 in a variety of clinical samples and proved sensitive in identifying viral RNA in samples from patients that had been declared negative using other nucleic acid-based assays (false negative). Sequencing the amplicons revealed that a number of patients had a proportion of viral genomes with deletions.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/virology , Pneumonia, Viral/virology , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , COVID-19 Vaccines , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , DNA, Complementary/analysis , DNA, Complementary/genetics , DNA, Viral/analysis , DNA, Viral/genetics , Genome, Viral , High-Throughput Nucleotide Sequencing/methods , Humans , Molecular Epidemiology , Multiplex Polymerase Chain Reaction , Pandemics , Pneumonia, Viral/diagnosis , RNA, Viral/analysis , RNA, Viral/genetics , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Sequence Analysis
6.
Viruses ; 12(10):1164, 2020.
Article in English | MDPI | ID: covidwho-855539

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Sequencing the viral genome as the outbreak progresses is important, particularly in the identification of emerging isolates with different pathogenic potential and to identify whether nucleotide changes in the genome will impair clinical diagnostic tools such as real-time PCR assays. Although single nucleotide polymorphisms and point mutations occur during the replication of coronaviruses, one of the biggest drivers in genetic change is recombination. This can manifest itself in insertions and/or deletions in the viral genome. Therefore, sequencing strategies that underpin molecular epidemiology and inform virus biology in patients should take these factors into account. A long amplicon/read length-based RT-PCR sequencing approach focused on the Oxford Nanopore MinION/GridION platforms was developed to identify and sequence the SARS-CoV-2 genome in samples from patients with or suspected of COVID-19. The protocol, termed Rapid Sequencing Long Amplicons (RSLAs) used random primers to generate cDNA from RNA purified from a sample from a patient, followed by single or multiplex PCRs to generate longer amplicons of the viral genome. The base protocol was used to identify SARS-CoV-2 in a variety of clinical samples and proved sensitive in identifying viral RNA in samples from patients that had been declared negative using other nucleic acid-based assays (false negative). Sequencing the amplicons revealed that a number of patients had a proportion of viral genomes with deletions.

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