Research on Malaria highlights

Malaria in Africa: What do mosquitoes with agene drives tell us about the situation in the West African landscape? A case study of A. gambiae

Researchers are questioning how mosquitoes with agene drives could affect the environment that they live in. Talya Hackett, an ecologist at the University of Oxford, UK, who works with Target Malaria, is assessing A. gambiae’s place in the food web in Ghana. “We’re looking to see if there’s anything that really is getting a large amount of its diet from Anopheles gambiae,” says Hackett. She does not think that will be the case. There aren’t many species that are expected to provide specialized food for one species of mosquito.

Malaria is caused by Plasmodium parasites that are transmitted from person to person by Anopheles mosquitoes — often Anopheles gambiae, the primary vector in sub-Saharan Africa. Many approaches to malaria control focus on mosquitoes. A massive part in reducing Malaria is the use of mosquito nets and indoor spraying of insecticides. But still it persists. The use of bed nets and spraying is having a great success, but it is not going to eliminate malaria, says Gregory Lanzaro, director of the University of California, Davis.

Using CRISPR to engineer the odds for genes to be safely inserted into a mosquito genome: An animal geneticist’s perspective

Gene drive was first proposed decades ago, in the context of naturally occurring selfish genetic elements — portions of DNA that enhance their own transmission. One example is sequences of DNA called transposable elements. These are found in a lot of organisms, including humans. Transposable elements can replicate on their own and integrate throughout an organism’s genome, causing them to be passed on to offspring at rates much higher than 50%.

The idea of using these portions of DNA to spread genes throughout a population of disease vectors, such as mosquitoes, was first proposed in the early 1990s2. However, researchers hit a problem: transposable elements would sometimes land in unfortunate places in an organism’s genome. The consequences of interrupting an existing genetic sequence by adding transposable elements can vary from the benign — changes in pigmentation in the medaka fish (Oryzias latipes)3, for example — to the decidedly harmful. It has been found that elements that are transposable into certain genes are linked to leukaemia and bone-marrow disease. The problem for researchers working on mosquito control was that the transposable elements would land somewhere in the insects’ genome that was immediately lethal, preventing the modification from being passed on. “We were working with that and we were just getting clobbered,” recalls molecular geneticist Anthony A. James at the University of California, Irvine.

After decades of trying to improve the insertion of selfish genes, the advent of CRISPR–Cas9 genome editing in 2012 finally gave scientists the tool they needed. The genetic sequence can be placed into the genome with these scissors. Researchers realized that if CRISPR–Cas9 was incorporated directly into an organism’s DNA, it would allow a gene to be safely copied from one generation to the next in perpetuity (see ‘Engineering the odds’).

Source: https://www.nature.com/articles/d41586-023-02051-4

Population-suppression approach to reducing the spread of A. gambiae and the disappearance of amphibians in sub-Saharan Africa

James, however, thinks that population replacement could be sufficient. He says it could come back even if the population of A. gambiae was suppressed. James sees replacement and suppression being used in tandem.

It would be difficult if mosquitoes with a gene drive were introduced into another country. The local people of sub-Saharan Africa would have to depend on the US team for hundreds of years to manage the gene drive. He thinks it sounds like colonialization.

She and her colleagues are looking into the possibility that the suppression of A. gambiae could result in an increase in other competing insect populations. Both genders feed on flower nectar but the mosquitos do not particularly interact with it. “They’re basically nectar robbers,” she says.

Hackett is optimistic about a population-suppression approach, partly because the ecological data look good, but also, she says, because it would target just one species of mosquito, unlike current broad-spectrum insecticidal toxins that are used for mosquito control. She says that the chemicals aren’t species specific. “As an ecologist, I’d say they have a huge amount of unintended consequences.”

The team, led by Colin Carlson, analysed the distribution of 22 species of mosquitoes in sub-Saharan Africa between 1898 and 2016 to assess the shifts in mosquito ranges that are already under way. The rates of mosquitoes traveling to high altitudes at an average of 6.5 metres per year and moving away from the Equator at a rate of only 4.7 kilometres per year have been shown by the results. Estimates for landbound species have been pegged at 1 metres elevation and 1.7 kilometres south per year.

Declines in amphibians have been reported for decades across multiple continents. The main culprit is thought to be Batrachochytrium dendrobatidis, a highly contagious fungus that infects the skin of amphibians and causes the disease chytridiomycosis. Because amphibians feed on the mosquitoes that transmit malaria to humans, it has been suggested that their decline could be behind spikes in malaria cases.

The findings support the idea that the warming climate is already changing the distribution of these infectious diseases. The authors warned that more work needs to be done to assess the extent of climate change to explain these observations.

Multistage Closure of Plasmodium falciparum in Malaria via a Novel Compound Known as Thenopyrimidines

A class of compound known as thienopyrimidines have been shown to kill Plasmodium falciparum parasites at multiple stages of their life cycle. The compounds clear both blood- and liver-stage parasites by targeting an enzyme known as cytoplasmic isoleucyl transfer RNA synthetase (cIRS). These could provide an alternative to malaria treatments based on artemisinin, which some parasites are resistant to.

The use of other compounds that target cIRS is limited due to drug toxicity. The compounds that the team investigated had low toxicity against human cell lines. The compounds block activity by binding to a different region of the cIRS. The researchers think that the multistage effects of these compounds, and the nature of the resistance-conferring mutations encountered during testing, means that there is little risk that substantial resistance will emerge.

The sexual phase of the development of Malaria parasites can be seen inside the mosquito. Parasite gametocytes are taken up by mosquitoes feeding on infected people, and then combine to form sporozoites — the form of the parasite that initially infects people. To generate sporozoites for use in vaccines, scientists have typically fed aseptic mosquitoes with blood infected with gametocytes, allowed the sporozoites to develop and then extracted and purified them from each mosquito’s salivary glands. This could make it difficult for the widespread use of chlorozoite-based vaccine, which have shown promise (see page S20).

To solve this problem, a team led by Stephen L. Hoffman at biotechnology firm Sanaria in Rockville, Maryland, processed gametocyte-containing blood in wells containing cells from the fruit fly, Drosophila melanogaster. It was the feeder cells that helped in the development of oocytes, which eventually resulted in millions of sporozoites.