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Fighting cerebral malaria with next-generation sequencing

Selasi Dankwa

Posted on Apr 24th, 2018

I remember distinctly all three times I was hospitalized with malaria as a child in Ghana. The chills, fatigue and nausea I experienced fade in my mind compared to the disappointment at missing out on fun activities at school. I am glad that my childlike mind did not know then what I know now all too well – that malaria kills, especially children. It is this knowledge that has spurred me on to study the pathogenesis of malaria in hopes of identifying ways to reduce or altogether prevent deaths from malaria.

One of the most dangerous complications that can arise from a malaria infection is cerebral malaria. This is when a person falls unconscious because malaria parasites are sticking to small blood vessels in the brain. In some cases, brain swelling occurs, a complication with a high risk of death. Cerebral malaria is especially difficult to study because of the inaccessibility of the brain while a person is living. But through creative application of new technologies, we are now one important step closer to preventing deaths from cerebral malaria.

In a large collaborative study, the Smith, Aitchison and Sather Labs at CIDR partnered with several others and recently uncovered the type of malaria parasite that is implicated in brain swelling in pediatric cerebral malaria. Our work also shed light on a potential mechanism by which malaria parasites cause brain swelling, opening up new avenues for drug intervention.

Working with scientists and physicians in the U.S. and in Blantyre, Malawi, this study was truly a multi-lab, multi-center, cross-country collaboration. It started in Blantyre, Malawi, where clinical samples provided valuable material to study and MRI imaging revealed the extent of brain swelling in patients. The study culminated in the application of next-generation sequencing to the study of cerebral malaria parasites.

What is next-generation sequencing?

Next-generation sequencing is the collective term given to newer sequencing technologies that allow multiple sequencing reactions to be run concurrently (“massively parallel sequencing”) in a relatively short period of time, resulting in a large amount of sequence data from a single run. Next-gen sequencing can be used to obtain the DNA sequence of an organism’s genome or the genomes of multiple microorganisms. Once prohibitively expensive, sequencing costs have declined steadily over the years, making it possible for individuals to have their own genomes sequenced as the concept of precision medicine gains popularity.

Using next-generation sequencing to fight malaria

In our particular application, we used next-gen sequencing to target a short segment of cDNA from parasites isolated directly from children suffering from malaria, including those with cerebral malaria with brain swelling. Next-gen sequencing gave us highly detailed information (akin to a barcode) on each type of parasite present, a decided advantage over the incomplete picture of parasite diversity that traditional sequencing methods provided.

Working backwards with this information, we were able to estimate the abundance of a specific parasite in the starting sample, based on the number of times that parasite’s sequence was present in the final pool of DNA. This information enabled us to predict the major binding pattern of parasites present in each patient.

The results strengthen the evidence that parasites that bind EPCR (a protein lining the surface of blood vessels), and specifically one particular type, are important in brain swelling in cerebral malaria.

It would have been extremely laborious and costly to have obtained similar data using the traditional Sanger sequencing method. Furthermore, we would have been less confident in our estimation of the abundance of specific parasite types, having only dozens of copies of the most abundant parasite types, compared to thousands of copies in the pool of sequenced DNA with next-generation sequencing.

Smarter research for a more hopeful future

While next-generation sequencing has been used before to study malaria parasites in severe pediatric malaria, use of this technology in such studies is still very new. I believe that the continued application of newer technologies to the study of malaria will significantly advance our understanding of the disease and help identify new ways to treat or prevent it. It will also eliminate the need for “brute force” approaches in research that are time and labor-intensive.

A generation has gone by since I was that child in Ghana, falling prey to malaria. A new generation is here, consisting of children like my nieces, who do not yet grasp the gravity of malaria but who will hopefully come to appreciate, once they do, the hope that our research brings.

It seems clear now that there will be no single magic bullet for cerebral malaria; however, through this study we have gained a better understanding of the parasites present in cerebral malaria cases and with that, potential pathways to target for therapeutic benefit. Ultimately, I hope that at some point in my lifetime – or my nieces’ – the complete eradication of malaria becomes a reality.

If you would like to learn more about researchers working on the front lines of the fight against malaria, check out our interviews with Dr. Terrie Taylor and Dr. Karl Seydel.

About the Author

Selasi’s interest in infectious diseases and human health led her to the Harvard School of Public Health where she received her PhD in Biological Sciences in Public Health. For her doctoral research, she studied invasion of red blood cells by malaria parasites, a process which is essential to the survival of the parasite in the host. As a postdoctoral scientist in the Smith Lab, she seeks to better understand vascular dysfunction in severe malaria, as well as how parasite genotypes and binding phenotypes relate to the severity of malaria in children. Selasi also enjoys the outdoors, reading and all things sweet.

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