Tag: malaria parasite

Credit: Free Vector Maps, DOI:
Sanger Science

Poised and waiting for malaria’s next move

12 September 2014
By Abdoulaye Djimdé

The cities where the PDNA member-institutions are located are indicated on the map of Africa.  Credit: DOI:

The cities where the PDNA member-institutions are located are indicated on the map of Africa. Credit: DOI:

Resistance to the widely used antimalarial drug artemisinin is spreading in Southeast Asia and is likely to be around the corner for Africa. It could reach us very quickly or it could emerge locally.

We don’t want to be surprised by it and we don’t want to be banging our heads against the wall trying to figure out how to deal with it when it comes. We need to be prepared.

To make sure we are, we’ve set up the African Plasmodium Diversity Network (PDNA), a group of scientists across the continent working together study malaria parasite genetics and track antimalarial drug resistance. This collaboration is an incredibly positive step that demonstrates our desire to reduce the burden of malaria in Africa.

The PDNA came about during a coffee break at the Genomic Epidemiology of Malaria conference at the Wellcome Trust Genome Campus in 2012. There were just four or five of us then, chatting about trying to set up a collaboration to look at parasite genetics in Africa. We didn’t know how this was going to play out but since that time, the PDNA has grown into a proactive and vibrant network of researchers from 12 different countries across the continent — and we plan to extend the network to better represent the diversity of sub-Saharan Africa.

Our hope is that by working together, undertaking regular monitoring at multiple sites, and sharing data through this network, we will be able to build a rich data resource and have a deep understanding of the genetic diversity of malaria parasites across Africa. It’s crucial that we begin this type of genomic surveillance now, as the landscape for malaria infection and transmission is changing very quickly.

A key first task for the PDNA is to survey parasite populations for the presence of the K13 molecular marker of artemisinin resistance, which was discovered late in 2013. Within months – a very short timeframe for work at this scale – PDNA scientists collected parasite samples that gave a good representation of their region, and then worked with Dominic Kwiatkowski’s team and others at the Wellcome Trust Sanger Institute to genotype the marker across the network sites. This study will provide valuable baseline data in Africa, and the findings are currently submitted for publication; a review article describing the PDNA more broadly has recently been published in Science.

Historically, drug resistance has emerged repeatedly in the same area of south-east Asia then spread to neighbouring countries and, eventually, to the rest of the world. If this happens again with artemisinin resistance, it will certainly take a much shorter time to reach Africa than it did in the past because travel between African and Asian capitals is so much more frequent and so much easier than it was five or 10 years ago. Also, there’s no reason to believe that there couldn’t be a local emergence of drug resistance.

Whenever and however the emergence of drug-resistant malaria parasite happens, the response will need to be quick. PDNA allows us to collect a large number of parasite samples across a huge geographical area and determine the DNA sequence in a matter of weeks.

This regular data collection will also make a big difference for my research in Mali. I work in parasite evolution and when we are dealing with the emergence of a rare genetic event we need a large sample size to pick it up. This network will generate enormous amounts of data, making our research and the research of many other scientists a lot easier.

Of course, these huge quantities of data also pose some challenges. Training will be crucial to developing our ability to analyse, handle and derive knowledge from these data sets. We plan to use bioinformatics specialists to train their peers within the network. We also intend to award PhD fellowships, giving very talented and carefully selected students the opportunity to have in-depth training so that our data handling remains state of the art.

This ambitious endeavour will enable African scientists to confidently advise our respective governments on the status of antimalarial drug resistance across Africa, allowing for quick action and intervention that will save lives.

Abdoulaye Djimdé is Associate Professor of Parasitology and Mycology and an International Fellow of the Sanger Institute (host institution is the University of Science,Techniques and Technologies of Bamako, Mali). He is interested in the genetic epidemiology of antimalarial drug resistance in Africa with a focus on how the genome variation in Plasmodium falciparum contributes to antimalarial drug resistance.

References

  • Ghansah, A et al (2014). African Plasmodium Diversity Network: genetic and phenotypic diversity for malaria elimination in sub-Saharan Africa. Science. DOI:10.1126/science.1259423

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Walking a thousand miles starts with one step

Malaria is a debilitating and sometimes fatal illness that is caused by infection with Plasmodium parasites and is passed between people by mosquitoes. Credit: Jim Gathany

11 September 2012

Written by Matthew Jones

3.3 billion people, over half of the world’s population, are at risk of malaria infection caused by the Plasmodium parasite. For those living in sub-Saharan Africa there is the added risk of severe disease and death because the most virulent Plasmodium species, Plasmodium falciparum, is the primary cause of disease. Adding to the severity of this public health problem is the continuing emergence of drug resistance—chloroquine, a cheap antimalarial used for decades to great effect is now mostly useless, and resistance to artemisinin, the now frontline defense against disease, is beginning to emerge. These factors combine to create an urgent need for a deeper understanding of Plasmodium parasites on many levels, from a practical level focused on finding new compounds that can be used as drugs, to a basic level focused on biological questions that will allow a deeper understanding of how these parasites cause disease.

The Malaria Programme at the Wellcome Trust Sanger Institute is carrying out research addressing questions both practical and fundamental, and as part of this programme, I have been working with the Institute’s Mass Spectrometry team to perform a large-scale analysis of protein palmitoylation in P. falciparum (http://dx.doi.org/10.1016/j.chom.2012.06.005). Protein palmitoylation is a tool that cells use to control specific protein-membrane interactions, and knowing which proteins in a cell are palmitoylated can give important clues about their regulation or function—clues that can be used to piece together new ideas about how cells work. In order to identify P. falciparum’s complement of palmitoylated proteins, we used a combination of palmitoyl-protein purification techniques and the latest in quantitative mass spectrometry techniques so that we could probe protein palmitoylation in great depth and with as much accuracy as is technically possible. In the end, this combination of techniques allowed us to identify more than 450 new palmitoyl-proteins—a significant achievement considering that before this work only 3 had been identified!

This new catalogue of P. falciparum palmitoyl-proteins is important for many reasons. For example, P. falciparum, especially when compared to laboratory model systems like yeast (which have a comparable number of genes), is an enigma; it’s proteome, the set of proteins expressed by its genome, is full of proteins with no known function, and large-scale studies like the one we have performed can shed light on processes that we currently know little or nothing about—a little like connecting pieces at the edge of a puzzle. To give a specific example, P. falciparum causes fatal disease largely because it is able to make infected red blood cells stick to blood-vessel walls. This ability depends on the parasite-driven wholesale reorganization of red blood cell structure, which P. falciparum is able to perform by exporting its own proteins into the red cell interior. What we have discovered, as a result of our analysis, is that P. falciparum palmitoylates a surprising number of the proteins that it exports. This is important because in most cases we don’t know what these exported proteins do, and we now have important clues about their function and regulation and can start to build hypotheses that probe an important disease-causing feature of P. falciparum biology.

To wrap up, on a basic level this work is important and will drive future research because the identification of 450-plus palmitoylated proteins immediately creates 450-plus specific questions (how does palmitoylation affect this specific protein?), but this work also brings up a number of related questions that deal with the means by which palmitoylation is accomplished, and how the proteins we have identified fit into their larger context to support parasite development. These questions will take years to address, but if walking a thousand miles starts with one step, then figuring out how P. falciparum works starts with one new experiment.

Matthew Jones is a Postdoctoral Fellow in Julian Rayner’s team, which is part of the Malaria Programme at the Wellcome Trust Sanger Institute more…

Review Article:

Matthew L. Jones, Mark O. Collins, David Goulding et al (2012) ‘Analysis of Protein Palmitoylation Reveals a Pervasive Role in Plasmodium Development and Pathogenesis’ Cell Host & Microbe, 12:246–258 http://dx.doi.org/10.1016/j.chom.2012.06.005

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Seq and ye shall find…

25 July 2012

Written by Lia Chappell

I’m studying for my PhD at the Sanger Institute and my interest is in understanding how the parasites responsible for malaria are able to adapt to live in both people and mosquitoes. I’m always looking for more effective, accurate and cost-efficient ways for us to see what is happening within the parasites’ cells.

Malaria parasites have a complicated life cycle, moving through different parts of the mosquito and human host, changing the shape of their single cell drastically in the process. This is impressive for an organism with about the same number of genes as a yeast cell that just floats around in it environment! To understand what happens when they change from one form to the next we can use a technology called RNA-seq. We can use RNA-seq to detect and count the RNA molecules present in a parasite (these are encoded in the genome, are made when genes are switched on, and control the amount of proteins being made). From this we can work out which genes and biological pathways are responsible for the parasite’s adaptability, which might help to identify targets for drug treatment.

RNA-seq is very useful at looking at the how much a gene is switched on in many types of living things, but the unusual nature the malaria parasite’s genome means it’s more challenging than most.

Recently I wrote a review called ‘Looking for a needle in a haystack’ in Nature Reviews Microbiology. The study I reviewed was particularly helpful because the researchers had taken the time to look carefully at a technological challenge. This problem can prevent many researchers from answering their questions or can make them blow their entire research budget on looking at molecules that aren’t of interest. They conducted a methodical comparison between technologies and manufacturers that many small laboratories would find too expensive to be able to carry out for themselves. I wanted to bring their work to the attention of a wider audience (who might not read as many method papers as me!) to highlight how important these details can be.

The authors of the study found that there are significant differences between processes and manufacturers in their ability to remove unwanted RNA molecules and increase the proportion of useful data produced. For example, one technology (Ribo-Zero) enriched RNA transcripts by up to 40-fold and increased useful data by as much as 98 per cent of the information sequenced. In addition, this particular technology also matched the relative abundances of molecules as those in the untreated controls. Others were less effective or, even worse, distorted the counts of different molecules (something you want to avoid when you are trying to compare the differing levels of gene expression).

I hope that my review encourages scientists to think carefully about the protocols that they use when using this technology to explore how genes work. It’s often hard to know which details you should focus on and spend your time and budget optimising, if the review helps my colleagues to spot potential biases and informs their choice of approach, then I will be very happy.

Lia Chappell is a PhD student in the Parasite Genomics team, studying gene expression in malaria… more

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