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Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae

16 February 2018 - 8:57am
Scientific Reports, Vol. 8, No. 1. (13 February 2018), doi:10.1038/s41598-018-21265-5
David Weetman, Craig Wilding, Daniel Neafsey, Pie Müller, Eric Ochomo, Alison Isaacs, Keith Steen, Emily Rippon, John Morgan, Henry Mawejje, Daniel Rigden, Loyce Okedi, Martin Donnelly
Categories: malaria news feeds

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

8 February 2018 - 11:45am
PLOS Genetics, Vol. 14, No. 1. (30 January 2018), e1007172, doi:10.1371/journal.pgen.1007172

Significant selection pressure has been exerted on the genomes of human populations exposed to Plasmodium falciparum infection, resulting in the acquisition of mechanisms of resistance against severe malarial disease. Many host genetic factors, including sickle cell trait, have been associated with reduced risk of developing severe malaria, but do not account for all of the observed phenotypic variation. Identification of novel inherited risk factors relies upon high-resolution genome-wide association studies (GWAS). We present findings of a GWAS of severe malaria performed in a Tanzanian population (n = 914, 15.2 million SNPs). Beyond the expected association with the sickle cell HbS variant, we identify protective associations within two interleukin receptors (IL-23R and IL-12RBR2) and the kelch-like protein KLHL3 (all P<10−6), as well as near significant effects for Major Histocompatibility Complex (MHC) haplotypes. Complementary analyses, based on detecting extended haplotype homozygosity, identified SYNJ2BP, GCLC and MHC as potential loci under recent positive selection. Through whole genome sequencing of an independent Tanzanian cohort (parent-child trios n = 247), we confirm the allele frequencies of common polymorphisms underlying associations and selection, as well as the presence of multiple structural variants that could be in linkage with these SNPs. Imputation of structural variants in a region encompassing the glycophorin genes on chromosome 4, led to the characterisation of more than 50 rare variants, and individually no strong evidence of associations with severe malaria in our primary dataset (P>0.3). Our approach demonstrates the potential of a joint genotyping-sequencing strategy to identify as-yet unknown susceptibility loci in an African population with well-characterised malaria phenotypes. The regions encompassing these loci are potential targets for the design of much needed interventions for preventing or treating malarial disease. Malaria, caused by Plasmodium falciparum parasites, is a major cause of mortality and morbidity in endemic countries of sub-Saharan Africa, including Tanzania. Some gene mutations in the human genome, including sickle cell trait, have been associated with reduced risk of developing severe malaria, and have increased in frequency through natural selection over generations. However, new genetic mutations remain to be discovered, and recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine-scale molecular genotyping tools, are facilitating their identification. Here, we present findings of a GWAS of severe malaria performed in a well characterised Tanzanian population (n = 914). We confirm the expected association with the sickle cell trait, but also identify new gene targets in immunological pathways, some under natural selection. Our approach demonstrates the potential of using GWAS to identify as-yet unknown susceptibility genes in endemic populations with well-characterised malaria phenotypes. The genetic mutations are likely to form potential targets for the design of much needed interventions for preventing or treating malarial disease.
Matt Ravenhall, Susana Campino, Nuno Sepúlveda, Alphaxard Manjurano, Behzad Nadjm, George Mtove, Hannah Wangai, Caroline Maxwell, Raimos Olomi, Hugh Reyburn, Christopher Drakeley, Eleanor Riley, Taane Clark, N in collaboration with MalariaGE
Categories: malaria news feeds

Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study

2 February 2018 - 9:09am
The Lancet Infectious Diseases (February 2018), doi:10.1016/s1473-3099(18)30068-9
Roberto Amato, Richard Pearson, Jacob Almagro-Garcia, Chanaki Amaratunga, Pharath Lim, Seila Suon, Sokunthea Sreng, Eleanor Drury, Jim Stalker, Olivo Miotto, Rick Fairhurst, Dominic Kwiatkowski
Categories: malaria news feeds

Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

1 February 2018 - 11:36am
Blood (01 January 2018), blood-2017-11-814665, doi:10.1182/blood-2017-11-814665
Souvik Bhattacharjee, Isabelle Coppens, Alassane Mbengue, Niraja Suresh, Mehdi Ghorbal, Zdenek Slouka, Innocent Safeukui, Hsin-Yao Tang, David Speicher, Robert Stahelin, Narla Mohandas, Kasturi Haldar
Categories: malaria news feeds

Proteomic analysis of extracellular vesicles from a Plasmodium falciparum Kenyan clinical isolate defines a core parasite secretome

19 January 2018 - 11:00am
Wellcome Open Research, Vol. 2 (22 November 2017), 50, doi:10.12688/wellcomeopenres.11910.2
Abdirahman Abdi, Lu Yu, David Goulding, Martin Rono, Philip Bejon, Jyoti Choudhary, Julian Rayner
Categories: malaria news feeds

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

18 January 2018 - 1:01pm
Science, Vol. 359, No. 6372. (12 January 2018), pp. 191-199, doi:10.1126/science.aan4472
Annie Cowell, Eva Istvan, Amanda Lukens, Maria Gomez-Lorenzo, Manu Vanaerschot, Tomoyo Sakata-Kato, Erika Flannery, Pamela Magistrado, Edward Owen, Matthew Abraham, Gregory LaMonte, Heather Painter, Roy Williams, Virginia Franco, Maria Linares, Ignacio Arriaga, Selina Bopp, Victoria Corey, Nina Gnädig, Olivia Coburn-Flynn, Christin Reimer, Purva Gupta, James Murithi, Pedro Moura, Olivia Fuchs, Erika Sasaki, Sang Kim, Christine Teng, Lawrence Wang, Aslı Akidil, Sophie Adjalley, Paul Willis, Dionicio Siegel, Olga Tanaseichuk, Yang Zhong, Yingyao Zhou, Manuel Llinás, Sabine Ottilie, Francisco-Javier Gamo, Marcus Lee, Daniel Goldberg, David Fidock, Dyann Wirth, Elizabeth Winzeler
Categories: malaria news feeds

Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax

11 January 2018 - 10:40am
Science, Vol. 359, No. 6371. (05 January 2018), pp. 48-55, doi:10.1126/science.aan1078
Jakub Gruszczyk, Usheer Kanjee, Li-Jin Chan, Sébastien Menant, Benoit Malleret, Nicholas Lim, Christoph Schmidt, Yee-Foong Mok, Kai-Min Lin, Richard Pearson, Gabriel Rangel, Brian Smith, Melissa Call, Michael Weekes, Michael Griffin, James Murphy, Jonathan Abraham, Kanlaya Sriprawat, Maria Menezes, Marcelo Ferreira, Bruce Russell, Laurent Renia, Manoj Duraisingh, Wai-Hong Tham
Categories: malaria news feeds

Cyclic nucleotide signalling in malaria parasites

11 January 2018 - 10:26am
Open Biology, Vol. 7, No. 12. (01 December 2017), 170213, doi:10.1098/rsob.170213
David Baker, Laura Drought, Christian Flueck, Stephanie Nofal, Avnish Patel, Maria Penzo, Eloise Walker
Categories: malaria news feeds

malERA: An updated research agenda for basic science and enabling technologies in malaria elimination and eradication

21 December 2017 - 10:28am
PLOS Medicine, Vol. 14, No. 11. (30 November 2017), e1002451, doi:10.1371/journal.pmed.1002451

Basic science holds enormous power for revealing the biological mechanisms of disease and, in turn, paving the way toward new, effective interventions. Recognizing this power, the 2011 Research Agenda for Malaria Eradication included key priorities in fundamental research that, if attained, could help accelerate progress toward disease elimination and eradication. The Malaria Eradication Research Agenda (malERA) Consultative Panel on Basic Science and Enabling Technologies reviewed the progress, continuing challenges, and major opportunities for future research. The recommendations come from a literature of published and unpublished materials and the deliberations of the malERA Refresh Consultative Panel. These areas span multiple aspects of the Plasmodium life cycle in both the human host and the Anopheles vector and include critical, unanswered questions about parasite transmission, human infection in the liver, asexual-stage biology, and malaria persistence. We believe an integrated approach encompassing human immunology, parasitology, and entomology, and harnessing new and emerging biomedical technologies offers the best path toward addressing these questions and, ultimately, lowering the worldwide burden of malaria.
The malERA Refresh Consultative Panel on Basic Science and Enabling Technologies
Categories: malaria news feeds

Profiling invasive Plasmodium falciparum merozoites using an integrated omics approach

15 December 2017 - 8:55am
Scientific Reports, Vol. 7, No. 1. (7 December 2017), doi:10.1038/s41598-017-17505-9
Krishan Kumar, Prakash Srinivasan, Michael Nold, Kathleen Moch, Karine Reiter, Dan Sturdevant, Thomas Otto, Burke Squires, Raul Herrera, Vijayaraj Nagarajan, Julian Rayner, Stephen Porcella, Scott Geromanos, David Haynes, David Narum
Categories: malaria news feeds

Impact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigation

14 December 2017 - 1:52pm
Proceedings of the National Academy of Sciences (11 December 2017), 201713814, doi:10.1073/pnas.1713814114
Hmooda Kafy, Bashir Ismail, Abraham Mnzava, Jonathan Lines, Mogahid Shiekh Eldin Abdin, Jihad Eltaher, Anuar Banaga, Philippa West, John Bradley, Jackie Cook, Brent Thomas, Krishanthi Subramaniam, Janet Hemingway, Tessa Knox, Elfatih Malik, Joshua Yukich, Martin Donnelly, Immo Kleinschmidt
Categories: malaria news feeds

Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors.

4 December 2017 - 9:00am
Nature (29 November 2017)

Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths each year. Plasmodium falciparum causes most life-threatening cases of malaria. Acquired immunity to malaria is inefficient, even after repeated exposure to P. falciparum, but the immune regulatory mechanisms used by P. falciparum remain largely unknown. Here we show that P. falciparum uses immune inhibitory receptors to achieve immune evasion. RIFIN proteins are products of a polymorphic multigene family comprising approximately 150-200 genes per parasite genome that are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibit activation of LILRB1-expressing B cells and natural killer (NK) cells. Furthermore, P. falciparum-infected erythrocytes isolated from patients with severe malaria were more likely to interact with LILRB1 than erythrocytes from patients with non-severe malaria, although an extended study with larger sample sizes is required to confirm this finding. Our results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.
Fumiji Saito, Kouyuki Hirayasu, Takeshi Satoh, Christian Wang, John Lusingu, Takao Arimori, Kyoko Shida, Nirianne Marie Palacpac, Sawako Itagaki, Shiroh Iwanaga, Eizo Takashima, Takafumi Tsuboi, Masako Kohyama, Tadahiro Suenaga, Marco Colonna, Junichi Takagi, Thomas Lavstsen, Toshihiro Horii, Hisashi Arase
Categories: malaria news feeds

Genetic diversity of the African malaria vector Anopheles gambiae

30 November 2017 - 1:52pm
Nature (29 November 2017), doi:10.1038/nature24995
Alistair Miles, Nicholas Harding, Giordano Bottà, Chris Clarkson, Tiago Antão, Krzysztof Kozak, Daniel Schrider, Andrew Kern, Seth Redmond, Igor Sharakhov, Richard Pearson, Christina Bergey, Michael Fontaine, Martin Donnelly, Mara Lawniczak, Dominic Kwiatkowski, Martin Donnelly, Diego Ayala, Nora Besansky, Austin Burt, Beniamino Caputo, Alessandra della Torre, Michael Fontaine, Godfray, Matthew Hahn, Andrew Kern, Dominic Kwiatkowski, Mara Lawniczak, Janet Midega, Daniel Neafsey, Samantha O’Loughlin, João Pinto, Michelle Riehle, Igor Sharakhov, Kenneth Vernick, David Weetman, Craig Wilding, Bradley White, Arlete Troco, João Pinto, Abdoulaye Diabaté, Samantha O’Loughlin, Austin Burt, Carlo Costantini, Kyanne Rohatgi, Nora Besansky, Nohal Elissa, João Pinto, Boubacar Coulibaly, Michelle Riehle, Kenneth Vernick, João Pinto, João Dinis, Janet Midega, Charles Mbogo, Philip Bejon, Craig Wilding, David Weetman, Henry Mawejje, Martin Donnelly, David Weetman, Craig Wilding, Martin Donnelly, Jim Stalker, Kirk Rockett, Eleanor Drury, Daniel Mead, Anna Jeffreys, Christina Hubbart, Kate Rowlands, Alison Isaacs, Dushyanth Jyothi, Cinzia Malangone, Paul Vauterin, Ben Jeffery, Ian Wright, Lee Hart, Krzysztof Kluczyński, Victoria Cornelius, Bronwyn MacInnis, Christa Henrichs, Rachel Giacomantonio, Dominic Kwiatkowski
Categories: malaria news feeds

Drug-resistant malaria: Molecular mechanisms and implications for public health

28 November 2017 - 12:56am
FEBS Letters, Vol. 585, No. 11. (06 June 2011), pp. 1551-1562, doi:10.1016/j.febslet.2011.04.042

Resistance to antimalarial drugs has often threatened malaria elimination efforts and historically has led to the short-term resurgence of malaria incidences and deaths. With concentrated malaria eradication efforts currently underway, monitoring drug resistance in clinical settings complemented by in vitro drug susceptibility assays and analysis of resistance markers, becomes critical to the implementation of an effective antimalarial drug policy. Understanding of the factors, which lead to the development and spread of drug resistance, is necessary to design optimal prevention and treatment strategies. This review attempts to summarize the unique factors presented by malarial parasites that lead to the emergence and spread of drug resistance, and gives an overview of known resistance mechanisms to currently used antimalarial drugs.
Ines Petersen, Richard Eastman, Michael Lanzer
Categories: malaria news feeds

Molecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25

23 November 2017 - 12:57pm
Nature Communications, Vol. 8, No. 1. (16 November 2017), doi:10.1038/s41467-017-01924-3
Stephen Scally, Brandon McLeod, Alexandre Bosch, Kazutoyo Miura, Qi Liang, Sean Carroll, Sini Reponen, Ngan Nguyen, Eldar Giladi, Sebastian Rämisch, Vidadi Yusibov, Allan Bradley, Franck Lemiale, William Schief, Daniel Emerling, Paul Kellam, Richter King, Jean-Philippe Julien
Categories: malaria news feeds

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

10 November 2017 - 9:25am
JCI Insight, Vol. 2, No. 21. (2 November 2017), doi:10.1172/jci.insight.96381
Ruth Payne, Sarah Silk, Sean Elias, Kazutoyo Miura, Ababacar Diouf, Francis Galaway, Hans de Graaf, Nathan Brendish, Ian Poulton, Oliver Griffiths, Nick Edwards, Jing Jin, Geneviève Labbé, Daniel Alanine, Loredana Siani, Stefania Di Marco, Rachel Roberts, Nicky Green, Eleanor Berrie, Andrew Ishizuka, Carolyn Nielsen, Martino Bardelli, Frederica Partey, Michael Ofori, Lea Barfod, Juliana Wambua, Linda Murungi, Faith Osier, Sumi Biswas, James McCarthy, Angela Minassian, Rebecca Ashfield, Nicola Viebig, Fay Nugent, Alexander Douglas, Johan Vekemans, Gavin Wright, Saul Faust, Adrian Hill, Carole Long, Alison Lawrie, Simon Draper
Categories: malaria news feeds

Molecular markers for artemisinin and partner drug resistance in natural Plasmodium falciparum populations following increased insecticide treated net coverage along the slope of mount Cameroon: cross-sectional study

9 November 2017 - 10:57am
Infectious Diseases of Poverty, Vol. 6, No. 1. (6 November 2017), doi:10.1186/s40249-017-0350-y
Tobias Apinjoh, Regina Mugri, Olivo Miotto, Hanesh Chi, Rolland Tata, Judith Anchang-Kimbi, Eleanor Fon, Delphine Tangoh, Robert Nyingchu, Christopher Jacob, Roberto Amato, Abdoulaye Djimde, Dominic Kwiatkowski, Eric Achidi, Alfred Amambua-Ngwa
Categories: malaria news feeds