Malaria kills a child every two minutes - and now mosquitoes are becoming resistant to insecticide

Wellcome Trust Sanger Institute in Hinxton sequences mosquito DNA to help tackle global scourge

Nearly half the world’s population is at risk of malaria – a disease that killed 445,000 people in 2016.

Of these, some 285,000 were African children who did not live to see their fifth birthday: it claims a child’s life every two minutes.

The use of insecticides as sprays and to treat bed nets has helped to reduce this horrific death toll on the continent since the turn of the century – but now mosquitoes are developing a resistance that threatens to derail malaria control.

In response, researchers at The Wellcome Trust Sanger Institute at Hinxton have been working with partners around the world to carry out the largest-ever genetic study of the insects. They have found extraordinary diversity – there were 52 million small differences in their genomes – along with the rapid evolution of several genes implicated in insecticide resistance.

Professor Martin Donnelly, who is collaborating with the Sanger Institute malaria programme and is a corresponding author of the new study from the Liverpool School of Tropical Medicine, said: “We know that mosquito populations are rapidly evolving resistance to insecticides, which is a serious threat to the future of malaria control in Africa.

“We have been able to see that a diverse array of genes linked to insecticide resistance are under very strong selection, confirming that they are playing an important role in the evolution of insecticide resistance in natural mosquito populations.

“Our study highlights the severe challenges facing public efforts to control mosquitoes and to manage and limit insecticide resistance.”

About 200 million people are infected with the malaria parasite around the globe each year. The majority of malaria deaths are in sub-Saharan Africa.

In 2014, the Wellcome Trust Sanger Institute established the Anopheles gambiae 1000 genomes project, supported by an international consortium of 20 research organisations.

Since then, the researchers have sequenced the DNA of 765 wild mosquitoes, taken from 15 locations across eight African nations. They have created the largest data resource on natural genetic variation for any insect species – and then examined each of the mosquitoes’ genomes.

The Sanger Institute’s Dr Mara Lawniczak, a corresponding author of a new paper on the project’s findings published in Nature, said: “The diversity of mosquito genomes was far greater than we expected. Such high levels of genetic variation poise mosquito populations to rapidly evolve in response to our efforts to control them, whether that be with insecticides or any other control measure, including gene drive.”

This latter measure involves using Crispr/Cas 9 genetic tools to make mosquitoes infertile or unable to carry the malaria parasite. To work, however, it requires an exact match with the targeted gene.

The study shows the variability means the approach is unlikely to work on most mosquito genes – but the data has highlighted less variable targets that could be more suitable for gene drive methods.

The genetic variation discovered in the Anopheles mosquito genomes is enabling the species to evolve rapidly and develop insecticide resistance.

The researchers were surprised to discover many previously unknown genetic variants within those genes that could be causing insecticide resistance. They found these variations emerging independently in different parts of Africa and, worryingly, being spread across the continent by mosquito migration.

The report’s lead author, Alistair Miles, of the Sanger Institute and the University of Oxford, said: “The data we have generated is a unique resource for studying how mosquito populations are responding to our current control efforts, and for designing better technologies and strategies for mosquito control in the future. More data will be needed to fill in the geographical gaps and study how mosquito populations change over time and in response to specific control interventions.

“However, this study demonstrates a clear path towards building a new and much-needed source of intelligence to support the campaign to eradicate malaria in Africa.”

The work involved scientists across centres in the United States, Italy, Russia, the Netherlands, France, Portugal and Gabon.

It was financially supported by the Wellcome Trust, Medical Research Council UK, the Department for International Development, the Foundation for the National Institutes of Health, the Bill & Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases.

The single-celled parasite causing untold human misery

The malaria parasite - a microscopic, single-celled organism called Plasmodium - is transmitted through the bite of infected female blood-sucking Anopheles mosquitoes.

Once injected from the mosquito’s saliva into a person’s blood, the parasite - in sporozoite (spore-like) form - heads straight to the liver.

Within 30 minutes the sporozoites have invaded the liver cells, where they develop into merozoites and rapidly multiply, producing thousands of merozoites.

They are usually in the liver cells for 10 days although some forms of the parasites can lie dormant in the liver for months or even years before being reactivated.

Bursting out of the liver, the merozoites invade red blood cells and multiply further. After 48 hours, their multiplication causes the red blood cells to burst, releasing more merozoites into the bloodstream, which in turn infect more red blood cells.

Over 10 days, some merozoites develop into the sexual form of the parasite, known as the gametocytes.

When another mosquito sucks up blood from an infected human, they take the gametocytes into them, where they mature, reproduce and form a thousand new sporozoites.

Billions spent to tackle malarial scourge – but little done to stop resistance

Preventative measures have helped halve the malaria burden in Africa since 2000 and saved six million lives.

Efforts stepped up in 2005, when US President George W Bush launched a malaria initiative to tackle the crisis and President Barack Obama doubled the funding for it when he came to office – investing $5.8 billion during his two terms, paying for tens of millions of homes to sprayed, insecticide-treated bednets to be purchased, anti-malaria treatments and rapid diagnostic tests.

But a paper published in the Lancet in 2015 by Prof Janet Hemingway, of the Liverpool School of Tropical Medicine, and others warned these efforts were not accompanied “plans to ensure the sustainability of these insecticide-based methods”.

It added: “Pyrethroids are the only class of insecticide recommended by the World Health Organisation for use on long-lasting insecticide-treated bednets.

“For more than a decade, mosquito vectors of malaria have been targeted with a monotherapy.

“Inevitably, resistance has been selected, and in some parts of Africa pyrethroids no longer kill mosquitoes. With no new insecticide class to replace the pyrethroids expected for a decade, the threat of resistance derailing malaria control has become an issue of urgency that can no longer be ignored without risking a global public health catastrophe.”

Between 2010 and 2015, 60 of the 78 countries monitoring it have reported mosquito resistance to at least one insecticide used in nets and indoor spraying and 49 have reported resistance to two or more insecticide classes.

The World Health Organisation has called developing nets using two different insecticides “a priority” to help reduce the spread of resistance and says several “promising products” for both indoor spraying and nets are in the pipeline.

Factfile

• 429,000 – estimated number of deaths from malaria in 2015

• 303,000 – number of under-fives in Africa who died from malaria that year – more than two-thirds of deaths

• 216 million – estimated number of malaria cases in 2016, up five million on the previous year

• 91 – number of countries reporting malaria cases in 2016

• Early diagnosis and prompt treatment helps saves lives and prevent further transmission

• Insecticide-treated bed nets are effective for 2-3 years and can be used to protect the most vulnerable, such as children and pregnant women

• Between 2010-15, the use of bed nets in sub-Saharan Africa increased by 80%

• Indoor spraying is effective for three-six months and works best when 80% of homes in an area are sprayed

• 5 – the number of children who will have died from malaria in the time it takes you to read this

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