JCI Insight, Vol. 2, No. 12. (15 June 2017), doi:10.1172/jci.insight.93683
Ruth Payne, Sarah Silk, Sean Elias, Kathryn Milne, Thomas Rawlinson, David Llewellyn, Rushdi Shakri, Jing Jin, Geneviève Labbé, Nick Edwards, Ian Poulton, Rachel Roberts, Ryan Farid, Thomas Jørgensen, Daniel Alanine, Simone de Cassan, Matthew Higgins, Thomas Otto, James McCarthy, Willem de Jongh, Alfredo Nicosia, Sarah Moyle, Adrian Hill, Eleanor Berrie, Chetan Chitnis, Alison Lawrie, Simon Draper

eLife, Vol. 6 (14 June 2017), doi:10.7554/elife.28600
Oliver Billker

Current pharmaceutical design, Vol. 19, No. 2. (2013), pp. 290-299

The most common treatments for infectious diseases target the invading pathogen. The efficacy of such an approach may, however, be countered by the possibility of the development of resistance to a pharmacophore, through mutation(s) in pathogen molecules required for activity. Given the fact that pathogens exploit host factors in order to grow in an otherwise hostile environment, one possible way to circumvent the emergence of resistance is to develop drugs that target non-essential host factors hijacked by the pathogen, rather than the pathogen's own molecules. Such solutions are already being developed for various viral and bacterial pathogens, but much less has been achieved with infections caused by protozoan parasites, as is the case of Plasmodium. Here, we highlight recent progress in host target-based anti-viral and anti-bacterial approaches and discuss possible host targets that may be used for anti-malarial interventions. Host molecules that play a role during either the liver or the blood stage of Plasmodium infection are outlined and their potential merits as anti-malarial targets are discussed.
Miguel Prudêncio, Maria Mota

Journal of Proteomics (June 2017), doi:10.1016/j.jprot.2017.06.002

Cerebral malaria (CM) is a severe neurological complication of malaria infection in both adults and children. In pursuit of effective treatment of CM, clinical studies, postmortem analysis and animal models have been employed to understand the pathology and identify effective interventions. In this study, a shotgun proteomics analysis was conducted to profile the proteomic signature of the brain tissue of mice with experimental cerebral malaria (ECM) in order to further understand the underlying pathology. To identify CM-associated response, proteomic signatures of the brains of C57/Bl6N mice infected with P. berghei ANKA that developed neurological syndrome were compared to those of mice infected with P. berghei NK65 that developed equally high parasite burdens without neurological signs, and to those of non-infected mice. The results show that the CM-associated response in mice that developed neurological signs comprise mainly acute-phase reaction and coagulation cascade activation, and indicate the leakage of plasma proteins into the brain parenchyma. Cerebral malaria (CM) remains a major cause of death in children. The majority of these deaths occur in sub-Saharan Africa. Even with adequate access to treatment, mortality remains high and neurological sequelae can be found in up to 20% of survivors. No adjuvant treatment to date has been shown to reduce mortality and the pathophysiology of CM is largely unknown. Experimental cerebral malaria (ECM) is a well-established model that may contribute to identify and test druggable targets. In this study we have identified the disruption of the blood-brain barrier following inflammatory and vascular injury as a mechanism of disease. In this study we report a number of proteins that could be validated as potential biomarkers of ECM. Further studies, will be required to validate the clinical relevance of these biomarkers in human CM.
Ehab Moussa, Honglei Huang, Malika Ahras, Amar Lall, Marie Thezenas, Roman Fischer, Benedikt Kessler, Arnab Pain, Oliver Billker, Climent Casals-Pascual

bioRxiv (29 May 2017), 141853, doi:10.1101/141853

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Priscila Rodrigues, Hugo Valdivia, Thais Oliveira, Joao Marcelo, Ana Maria, Crispim Cerutti-Junior, Julyana Buery, Cristiana Brito, Julio Souza, Zelinda Maria Braga Hirano, Rosely Malafronte, Simone Ladeia-Andrade, Toshihiro Mita, Ana Santamaria, Jose Calzada, Fumihiko Kawamoto, Leonie Raijmakers, Ivo Mueller, Maria Pacheco, Ananias Escalante, Ingrid Felger, Marcelo Ferreira

The Journal of infectious diseases (25 May 2017)

Human malaria susceptibility is determined by multiple genetic factors. It is however unclear which genetic variants remain important over time. Genetic associations of 175 high quality polymorphisms within several malaria candidate genes were examined in a sample of 8,096 individuals from northeast Tanzania using altitude, seroconversion rates and parasite rates as proxies of historical, recent and current malaria transmission intensity. A principal component (PC) analysis was used to derive two alternative measures of overall malaria propensity of a location across different time scales. Common red blood cell polymorphisms (i.e., HbS, G6PD and α-thalassaemia) were the only ones to be associated with all three measures of transmission intensity and the first PC. Moderate associations were found between some immune response genes (i.e., IL3 and IL13) and parasite rates, but these could not be reproduced using the alternative measures of malaria propensity. We have demonstrated the potential of using altitude and seroconversion rate as measures of malaria transmission capturing medium to long term time scales to detect genetic associations that are likely to persist over time. These measures also have the advantage of minimizing the deleterious effects of random factors affecting parasite rates on the respective association signals.
Nuno Sepúlveda, Alphaxard Manjurano, Susana Campino, Martha Lemnge, John Lusingu, Raimos Olomi, Kirk Rockett, Christina Hubbart, Anna Jeffreys, Kate Rowlands, , Taane Clark, Eleanor Riley, Chris Drakeley

Human Molecular Genetics, Vol. 26, No. 7. (01 April 2017), pp. 1391-1406, doi:10.1093/hmg/ddx036
Amy Jones, Mera Tilley, Alex Gutteridge, Craig Hyde, Michael Nagle, Daniel Ziemek, Donal Gorman, Eric Fauman, Xing Chen, Melissa Miller, Chao Tian, Youna Hu, David Hinds, Peter Cox, Serena Scollen

Science (18 May 2017), eaam6393, doi:10.1126/science.aam6393
Ellen Leffler, Gavin Band, George Busby, Katja Kivinen, Quang Le, Geraldine Clarke, Kalifa Bojang, David Conway, Muminatou Jallow, Fatoumatta Sisay-Joof, Edith Bougouma, Valentina Mangano, David Modiano, Sodiomon Sirima, Eric Achidi, Tobias Apinjoh, Kevin Marsh, Carolyne Ndila, Norbert Peshu, Thomas Williams, Chris Drakeley, Alphaxard Manjurano, Hugh Reyburn, Eleanor Riley, David Kachala, Malcolm Molyneux, Vysaul Nyirongo, Terrie Taylor, Nicole Thornton, Louise Tilley, Shane Grimsley, Eleanor Drury, Jim Stalker, Victoria Cornelius, Christina Hubbart, Anna Jeffreys, Kate Rowlands, Kirk Rockett, Chris Spencer, Dominic Kwiatkowski, Malaria Genomic Epidemiology Network

Wellcome Open Research, Vol. 2 (20 April 2017), 29, doi:10.12688/wellcomeopenres.11228.1
Irene Omedo, Polycarp Mogeni, Kirk Rockett, Alice Kamau, Christina Hubbart, Anna Jeffreys, Lynette Ochola-Oyier, Etienne de Villiers, Caroline Gitonga, Abdisalan Noor, Robert Snow, Dominic Kwiatkowski, Philip Bejon

Malaria Journal, Vol. 16, No. 1. (12 May 2017), doi:10.1186/s12936-017-1845-5
Angana Mukherjee, Selina Bopp, Pamela Magistrado, Wesley Wong, Rachel Daniels, Allison Demas, Stephen Schaffner, Chanaki Amaratunga, Pharath Lim, Mehul Dhorda, Olivo Miotto, Charles Woodrow, Elizabeth Ashley, Arjen Dondorp, Nicholas White, Dyann Wirth, Rick Fairhurst, Sarah Volkman

eLife, Vol. 6 (may 2017), e26524, doi:10.7554/elife.26524

Malaria transmission relies on the production of gametes following ingestion by a mosquito. Here, we show that Ca2+-dependent protein kinase 4 controls three processes essential to progress from a single haploid microgametocyte to the release of eight flagellated microgametes in Plasmodium berghei. A myristoylated isoform is activated by Ca2+ to initiate a first genome replication within twenty seconds of activation. This role is mediated by a protein of the SAPS-domain family involved in S-phase entry. At the same time, CDPK4 is required for the assembly of the subsequent mitotic spindle and to phosphorylate a microtubule-associated protein important for mitotic spindle formation. Finally, a non-myristoylated isoform is essential to complete cytokinesis by activating motility of the male flagellum. This role has been linked to phosphorylation of an uncharacterised flagellar protein. Altogether, this study reveals how a kinase integrates and transduces multiple signals to control key cell-cycle transitions during Plasmodium gametogenesis.
Hanwei Fang, Natacha Klages, Bastien Baechler, Evelyn Hillner, Lu Yu, Mercedes Pardo, Jyoti Choudhary, Mathieu Brochet

Science Translational Medicine, Vol. 9, No. 387. (26 April 2017), eaad9735, doi:10.1126/scitranslmed.aad9735
Tanya Paquet, Claire Le Manach, Diego Cabrera, Yassir Younis, Philipp Henrich, Tara Abraham, Marcus Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew Blagborough, Sara Zakutansky, Anne-Marie Zeeman, Karen White, David Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Martínez, Santiago Ferrer, Laura Sanz, Francisco Gamo, Janette Reader, Mariette Botha, Koen Dechering, Robert Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Lim, Jeremy Burrows, Michael Witty, Kennan Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh Solapure, María Jiménez-Díaz, Sergio Wittlin, Susan Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten Hanson, Gerard Drewes, Clemens Kocken, Michael Delves, Didier Leroy, David Fidock, David Waterson, Leslie Street, Kelly Chibale

Malaria Journal, Vol. 16, No. 1. (28 April 2017), doi:10.1186/s12936-017-1826-8
Rhea Longley, Camila França, Michael White, Chalermpon Kumpitak, Patiwat Sa-angchai, Jakub Gruszczyk, Jessica Hostetler, Anjali Yadava, Christopher King, Rick Fairhurst, Julian Rayner, Wai-Hong Tham, Wang Nguitragool, Jetsumon Sattabongkot, Ivo Mueller

Emerging Infectious Diseases, Vol. 23, No. 8. (August 2017), doi:10.3201/eid2308.161582
Gavin Rutledge, Ian Marr, Huang, Sarah Auburn, Jutta Marfurt, Mandy Sanders, Nicholas White, Matthew Berriman, Chris Newbold, Nicholas Anstey, Thomas Otto, Ric Price

Scientific Reports, Vol. 7 (25 April 2017), 46674, doi:10.1038/srep46674
Alison Isaacs, Amy Lynd, Martin Donnelly

Scientific Reports, Vol. 7 (18 April 2017), 46451, doi:10.1038/srep46451
José Vicente, Christopher Clarkson, Beniamino Caputo, Bruno Gomes, Marco Pombi, Carla Sousa, Tiago Antao, João Dinis, Giordano Bottà, Emiliano Mancini, Vincenzo Petrarca, Daniel Mead, Eleanor Drury, James Stalker, Alistair Miles, Dominic Kwiatkowski, Martin Donnelly, Amabélia Rodrigues, Alessandra Torre, David Weetman, João Pinto

Genome Research (17 April 2017), gr.217356.116, doi:10.1101/gr.217356.116

An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms
Heather Painter, Manuela Carrasquilla, Manuel Llinás

J. Chem. Inf. Model., Vol. 57, No. 3. (27 March 2017), pp. 445-453, doi:10.1021/acs.jcim.6b00572

The development of new antimalarial therapies is essential, and lowering the barrier of entry for the screening and discovery of new lead compound classes can spur drug development at organizations that may not have large compound screening libraries or resources to conduct high-throughput screens. Machine learning models have been long established to be more robust and have a larger domain of applicability with larger training sets. Screens over multiple data sets to find compounds with potential malaria blood stage inhibitory activity have been used to generate multiple Bayesian models. Here we describe a method by which Bayesian quantitative structure–activity relationship models, which contain information on thousands to millions of proprietary compounds, can be shared between collaborators at both for-profit and not-for-profit institutions. This model-sharing paradigm allows for the development of consensus models that have increased predictive power over any single model and yet does not reveal the identity of any compounds in the training sets.
Andreas Verras, Chris Waller, Peter Gedeck, Darren Green, Thierry Kogej, Anandkumar Raichurkar, Manoranjan Panda, Anang Shelat, Julie Clark, Kiplin Guy, George Papadatos, Jeremy Burrows

Malaria Journal, Vol. 16, No. 1. (5 April 2017), doi:10.1186/s12936-017-1784-1
Kamala Thriemer, Benedikt Ley, Albino Bobogare, Lek Dysoley, Mohammad Alam, Ayodhia Pasaribu, Jetsumon Sattabongkot, Elodie Jambert, Gonzalo Domingo, Robert Commons, Sarah Auburn, Jutta Marfurt, Angela Devine, Mohammad Aktaruzzaman, Nayeem Sohel, Rinzin Namgay, Tobgyel Drukpa, Surender Sharma, Elvieda Sarawati, Iriani Samad, Minerva Theodora, Simone Nambanya, Sonesay Ounekham, Rose Mudin, Garib Da Thakur, Leo Makita, Raffy Deray, Sang-Eun Lee, Leonard Boaz, Manjula Danansuriya, Santha Mudiyanselage, Nipon Chinanonwait, Suravadee Kitchakarn, Johnny Nausien, Esau Naket, Thang Duc, Ha Do Manh, Young Hong, Qin Cheng, Jack Richards, Rita Kusriastuti, Ari Satyagraha, Rintis Noviyanti, Xavier Ding, Wasif Khan, Ching Swe Phru, Zhu Guoding, Gao Qi, Akira Kaneko, Olivo Miotto, Wang Nguitragool, Wanlapa Roobsoong, Katherine Battle, Rosalind Howes, Arantxa Roca-Feltrer, Stephan Duparc, Ipsita Bhowmick, Enny Kenangalem, Jo-Anne Bibit, Alyssa Barry, David Sintasath, Rabindra Abeyasinghe, Carol Sibley, James McCarthy, Lorenz von Seidlein, Kevin Baird, Ric Price

bioRxiv (10 April 2017), 126276, doi:10.1101/126276

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Brandon Invergo, Mathieu Brochet, Lu Yu, Jyoti Choudhary, Pedro Beltrao, Oliver Billker