Malaria

The Malaria programme integrates genomic, genetic and proteomic approaches to tackle fundamental questions in malaria biology, and to identify new targets for drug and vaccine development.

The Malaria programme develops and applies high throughput and large-scale platforms to significantly expand our understanding of natural genetic variation in human hosts, Plasmodium parasites and Anopheles vector populations; to enable large-scale genetic modification of Plasmodium parasites; and to identify host-parasite protein-protein interactions. We collaborate closely with other Sanger research programmes, particularly Pathogen Genetics, Cellular Genetics and Human Genetics.

  • Projects - a list of Faculty-led research projects in Malaria
  • Collaborations and resources - a list of collaborations and resources in which the Malaria programme plays a leading role

[Genome Research Limited]

Background

Mosquitoes carry Plasmodium parasites that cause more than half a million deaths each year, primarily in children under the age of five in sub-Saharan Africa.

Mosquitoes carry Plasmodium parasites that cause more than half a million deaths each year, primarily in children under the age of five in sub-Saharan Africa. [Wellcome Library, London]

Malaria is a debilitating and sometimes fatal illness that is caused by infection with Plasmodium parasites that are passed between people by Anopheles mosquitoes. Despite progress in fighting the illness, nearly half the world's population - 3.4 billion people in 97 countries - are at risk. In 2012, there were 207 million reported cases and 627,000 deaths, with the majority of deaths among African children under the age of five (WHO Malaria Report, 2013). Developing an effective malaria vaccine and fighting antimalarial drug resistance remain major global public health challenges.

By integrating genomics with experimental research and operating both at scale, the Malaria programme is uniquely placed to tackle key challenges in malaria control, including the development of effective genomic surveillance of drug and insecticide resistance, and identifying and validating new drug and vaccine targets.

Research

Natural genetic variation

Malaria parasites and their mosquito vectors are continually and rapidly evolving. Disease control efforts, whether through drugs or insecticides, routinely lead to the emergence of resistance and the rebound of disease in a less controllable form.

This evolutionary struggle can be monitored in real time by studying natural genetic variation in all three genomes involved in malaria - the Plasmodium parasites that cause the illness, the Anopheles mosquitoes that transmit the parasites, and the human hosts.

Sequencing the genome of Plasmodium falciparum, the parasite that causes almost all deaths from malaria, was one of the earliest projects embarked on at the Sanger Institute. Recent changes in technology allow us to move from sequencing a single genome to sequencing the genomes of large numbers of parasites obtained directly from infected patients.

Over the past five years, the Malaria programme formed key partnerships and developed the technical and analytical infrastructure to support large-scale analysis of genome variation. As result, we've built rich data resources that can now be used to characterise the biological and clinical consequences of natural genetic variation. We can investigate whether specific gene variants are associated with certain outcomes, such as identifying genes associated with drug resistance. The same approach can be used to identify mosquito genes associated with insecticide resistance, or human genes associated with protection against severe malaria. Through our collaborations with the Centre for Genomics and Global Health and Malaria Genomic Epidemiology Network (MalariaGEN), we are working with researchers from all around the world to power these new studies.

Experimental genetics

The genome sequences of pathogens such as malaria parasites by definition contain all the possible genes that could be targeted by drugs and vaccines. We are using experimental approaches to move from this long list of possible targets - more than 5,000 genes in the case of most Plasmodium genomes - to a short list of high priority targets. Identifying these targets requires both a deep understanding of parasite biology and systematic approaches that can be scaled to all genes in the genome.

For the past two decades, researchers have used genetic technologies to delete individual genes and measure the impact on parasite growth. We have now developed new high-throughput tools for experimental genetic manipulation of Plasmodium parasites, including the ability to screen more than 100 genes in a single experiment. We are now using these tools to perform systematic whole genome screens in Plasmodium parasites. Libraries of gene targeting vectors and the methods to use them are made freely available to the wider research community through the Plasmodium Genetic Modification (PlasmoGEM) project.

We are also developing new approaches to identify the host-parasite interactions that allow Plasmodium parasites to recognise and invade human red blood cells. Such interactions are high priority vaccine targets, as if we can prevent a parasite from entering a human cell, we can prevent disease. However for technical reasons, including the unusual nature of Plasmodium proteins, these interactions have previously proven difficult to identify. New technologies developed at the Sanger Institute have recently identified several new interactions, including one that appears to be essential for red blood cell invasion. We are working in collaboration with partners in Kenya and Oxford to pursue the potential of these as vaccine candidates.

Selected Publications

  • Reappraisal of known malaria resistance loci in a large multicenter study.

    Malaria Genomic Epidemiology Network and Malaria Genomic Epidemiology Network

    Nature genetics 2014;46;11;1197-204

  • Monitoring parasite diversity for malaria elimination in sub-Saharan Africa.

    Ghansah A, Amenga-Etego L, Amambua-Ngwa A, Andagalu B, Apinjoh T, Bouyou-Akotet M, Cornelius V, Golassa L, Andrianaranjaka VH, Ishengoma D, Johnson K, Kamau E, Maïga-Ascofaré O, Mumba D, Tindana P, Tshefu-Kitoto A, Randrianarivelojosia M, William Y, Kwiatkowski DP and Djimde AA

    Science (New York, N.Y.) 2014;345;6202;1297-8

  • A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

    Sinha A, Hughes KR, Modrzynska KK, Otto TD, Pfander C, Dickens NJ, Religa AA, Bushell E, Graham AL, Cameron R, Kafsack BF, Williams AE, Llinás M, Berriman M, Billker O and Waters AP

    Nature 2014;507;7491;253-7

  • Adaptive introgression between Anopheles sibling species eliminates a major genomic island but not reproductive isolation.

    Clarkson CS, Weetman D, Essandoh J, Yawson AE, Maslen G, Manske M, Field SG, Webster M, Antão T, MacInnis B, Kwiatkowski D and Donnelly MJ

    Nature communications 2014;5;4248

  • Genome sequencing of chimpanzee malaria parasites reveals possible pathways of adaptation to human hosts.

    Otto TD, Rayner JC, Böhme U, Pain A, Spottiswoode N, Sanders M, Quail M, Ollomo B, Renaud F, Thomas AW, Prugnolle F, Conway DJ, Newbold C and Berriman M

    Nature communications 2014;5;4754

  • Vector transmission regulates immune control of Plasmodium virulence.

    Spence PJ, Jarra W, Lévy P, Reid AJ, Chappell L, Brugat T, Sanders M, Berriman M and Langhorne J

    Nature 2013;498;7453;228-31

  • Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia.

    Miotto O, Almagro-Garcia J, Manske M, Macinnis B, Campino S, Rockett KA, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Duong S, Nguon C, Chuor CM, Saunders D, Se Y, Lon C, Fukuda MM, Amenga-Etego L, Hodgson AV, Asoala V, Imwong M, Takala-Harrison S, Nosten F, Su XZ, Ringwald P, Ariey F, Dolecek C, Hien TT, Boni MF, Thai CQ, Amambua-Ngwa A, Conway DJ, Djimdé AA, Doumbo OK, Zongo I, Ouedraogo JB, Alcock D, Drury E, Auburn S, Koch O, Sanders M, Hubbart C, Maslen G, Ruano-Rubio V, Jyothi D, Miles A, O'Brien J, Gamble C, Oyola SO, Rayner JC, Newbold CI, Berriman M, Spencer CC, McVean G, Day NP, White NJ, Bethell D, Dondorp AM, Plowe CV, Fairhurst RM and Kwiatkowski DP

    Nature genetics 2013;45;6;648-55

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

    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

    Nature 2012;487;7407;375-9

  • Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum.

    Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC and Wright GJ

    Nature 2011;480;7378;534-7

  • A scalable pipeline for highly effective genetic modification of a malaria parasite.

    Pfander C, Anar B, Schwach F, Otto TD, Brochet M, Volkmann K, Quail MA, Pain A, Rosen B, Skarnes W, Rayner JC and Billker O

    Nature methods 2011;8;12;1078-82

  • Origin of the human malaria parasite Plasmodium falciparum in gorillas.

    Liu W, Li Y, Learn GH, Rudicell RS, Robertson JD, Keele BF, Ndjango JB, Sanz CM, Morgan DB, Locatelli S, Gonder MK, Kranzusch PJ, Walsh PD, Delaporte E, Mpoudi-Ngole E, Georgiev AV, Muller MN, Shaw GM, Peeters M, Sharp PM, Rayner JC and Hahn BH

    Nature 2010;467;7314;420-5

Training

Malaria Experimental Genetics courses

Each year, the Malaria programme hosts a Wellcome Trust Advanced Course on Malaria Experimental Genetics. This week-long, laboratory-based course gives participants a working knowledge of and practical experience in cutting-edge Plasmodium experimental genetics techniques, from designing gene targeting vectors and creating transgenic parasites to phenotyping the strains that result. The goal is to facilitate the participants' own research careers by exposing them to state-of-the-art experimental approaches, while discussing the advantages and limitations of each approach. For more information, visit the Wellcome Trust Advanced Courses website.

Genomic Epidemiology of Malaria courses

The Malaria programme has also hosted a number of Wellcome Trust Advanced Courses and other training courses on the Genomic Epidemiology of Malaria. Designed to build capacity for population genetics and genome-wide association studies in malaria-endemic areas, many of these courses were hosted overseas including in Uganda, Thailand, and Kenya.

Public engagement

The Malaria Programme is strongly committed to public engagement and broader education efforts to bring a better understanding of malaria to the general public. Notable past projects include:

Malaria Challenge

Developed with the Genome Campus Public Engagement team, this multi-media resource is designed to introduce the Plasmodium lifecycle to youth aged 14 or older, and is freely available on the Your Genome website. Malaria Challenge uses animation, microscopy images, teacher work plans and interviews with malaria researchers to produce an interactive and detailed resource designed to facilitate understanding of the science behind Plasmodium parasite biology.

Royal Society Summer Science Exhibition

We were actively involved with the Sanger Institute exhibit at 2013 Royal Society Summer Science Exhibition. The Malaria programme was one of four present-day projects used to illustrate the role of genomics in improved public health. As part of the exhibit, we also developed a short animation to explain how the study of natural genetic variation in Plasmodium parasites can help researchers to understand and track antimalarial drug resistance. Watch the animation on the MalariaGEN YouTube channel.

Projects

*Cell surface signalling laboratory
Gavin Wright's team aims to discover entirely new host-parasite interactions by identifying novel cell surface receptor-ligand pairs
*Erythrocyte-parasite interactions
Julian Rayner's team investigates the interactions between Plasmodium parasites and human red blood cells
*Natural genetic variation and malaria
Dominic Kwiatkowski's team investigates biological consequences of natural genetic variation in the human, Plasmodium and Anopheles genomes
*Parasite genomics
Matt Berriman's team uses sequencing to uncover the genomic basis for differences in the biology of strains or species of parasites including Plasmodium
*Rodent models of malaria
Oliver Billker's team elucidates the molecular and cell biology of malaria parasites to understand their development and transmission
*Vector-parasite interactions
Mara Lawniczak's team investigates the underlying genetic variations that make some mosquitoes better than others at transmitting the malaria parasites they carry to humans

Collaborations and resources

*Centre for Genomics and Global Health (CGGH)
The CGGH accelerates the translation of large-scale genomic data into meaningful information and effective tools to combat infectious diseases endemic in the developing world
*LookSeq
A web-based application for alignment visualisation, browsing and analysis of genome sequence data
*MalariaGEN
The Malaria Genomic Epidemiology Network is a data-sharing community working to develop new tools to control malaria by integrating epidemiology with genome science
*PlasmoGEM
The Plasmodium Genetic Modification Project produces and distributes free tools for the genetic manipulation of malaria parasites for research purposes
*Sequencing
The Institute harnesses cutting-edge technologies to generate DNA sequence in order to answer questions about biology and disease

Faculty

Matt's photo Dr Matt Berriman
Matt's profile

Oliver's photo Dr Oliver Billker
Oliver's profile

Dominic's photo Prof Dominic Kwiatkowski
Dominic's profile

Julian's photo Dr Julian Rayner
Julian's profile

Gavin's photo Dr Gavin Wright
Gavin's profile

Mara's photo Dr Mara Lawniczak
Mara's profile

Honorary Faculty

Martin's photo Dr Martin Donnelly
Martin's profile

Chris's photo Prof Chris Newbold
Chris' profile

International Fellow

Djimde's photo Dr Abdoulaye Djimdé
Djimdé's profile

* quick link - http://q.sanger.ac.uk/0vn3xy3c