Part One: Could a spider-toxin weaponised fungus fight Malaria?

Malaria infects over 200 million people each year and is the cause of hundreds of thousands of deaths, with mosquitoes becoming insecticide resistant and questions being raised on how insecticides could impact human health, what are our next steps?

This is second in a series, Alternative methods to fight Mosquito-borne diseases
Part One: Could a spider-toxin weaponised fungus fight Malaria?
Part Two: Could “friendly” mosquitoes defend the vulnerable?

Malaria is caused by a single-celled parasite named Plasmodium and is spread by female Anopheles mosquitoes. Males do not bite humans, but the females need blood to nourish their eggs after mating, but when they feed from a human that is already infected with Malaria they pick up the parasite themselves. The parasite then multiplies in their midgut before migrating to the salivary glands. Here they are in prime position to be injected into the skin of the next human the mosquito bites, thus infecting the new host and exacerbating the spread.

There are 460 species of Anopheles mosquitoes, and insect-bitesof this number only 100 can carry the 5 species of Plasmodium that infect humans (P. falciparum, P. malariae, P. vivax, P. ovale and P. knowlesi). Only 3 or 4 dozen pose a risk to humans by being efficient carriers and only a few of those prefer humans’ blood to other blood sources. Of the 460 species only 5 carry P. falciparum, which is the species responsible for the most deaths worldwide.

Mosquitoes are becoming increasingly resistant to insecticides, compelling researchers to develop novel countermeasures. An unorthodox approach involves enlisting the help of a fungus. There are many species of fungi that infect insects and consume their bodies in order to reproduce and are called Netomopathogenic fungi. Researchers from the University of Maryland and the IRSS institute in Burkino Faso identified such a fungus, but found it selectively infecting and killing Anopheles mosquitoes while mercifully leaving other insect life alone.

When a Metarhizium pingshaense spore encounters an insect, it produces a sticky structure called an appressorium to attach itself to the surface. This then secretes enzymes so the fungus can burrow through the cuticle and reach the haemolymph, which is the insect equivalent to blood. To shield itself from the insect’s immune system it then hides itself with a collagenous coat, and it is this genetic regulation of only activating when in contact with the haemolymph that can be leveraged. Although the wild-type M. pingshaense kills mosquitoes, it does so slowly and must infect them with a high dose of spores to be lethal, so researchers inserted the gene for a species of Funnel-web spiders’ toxin into the fungus’ genetic code. Using the collagenous coat promoter, the toxin was programmed to only be produced only when the fungus comes into contact with haemolymph. The genetically enhanced fungus, termed Mp-Hybrid, performed well in the laboratory against the Mp-WT but the next step was a field test. 

MosquitoSphere Etienne BilgoA semi-field environment emulating natural conditions coined a “MosquitoSphere” was built. The “sphere” had a double layer of netting to prevent any escapees while allowing ambient air movement and contained huts and water sources. The fungus was suspended in sesame oil and spread onto black cotton sheets that were then hung up in the huts. Working with locals, the researchers collected insecticide-resistant larvae and raised them in controlled conditions. When the MosquitoSphere was ready, 1000 males and 500 females were released into three different sections: one containing no fungus as a control, one the Mp-WT, and one the Mp-Hybrid. After 45 days (2 generations of mosquitoes) there were 2500 mosquitoes in the control section, 700 in the Mp-WT section, and only 13 in the Mp-Hybrid section. This trial was repeated twice more during the rainy season and found very similar results, Mp-Hybrid killed mosquitoes at a much lower lethal dose and showed better long-term control of the population than the parental strain. After 2 generations to population effectively collapsed as the males cannot form the swarm required for mating.

TheWeigo Fang researchers also found that after exposure to the Mp-Hybrid, the dying mosquitoes brought forward their oviposition schedule to possibly “compensate for reduced chances of future reproduction… This is the first time it has been shown that transgene expression can induce an increased terminal investment response, potentially undermining transgenic control approaches by affecting the evolution of infected mosquitos”. Although the effects of Mp-Hybrid counteracted this response by resulting in fewer progeny, this could be a potential drawback to genetically modified solutions and should be considered in future studies.

Genetically modified organisms always bring up concerns of unauthorized spreading from its release point and harming fragile ecosystems, but the researchers are confident this would be unlikely. The spores are sticky, large, UV-sensitive, and aren’t naturally dispersed by the air, so will be unlikely to spread for the building interiors they are applied to. The fungus sporulates when it has consumed all the tissue/nutrients it can and erupts from its cadaver, but scavengers and predators should take care of the cadavers before sporulation occurs. Metarhizium biopesticides are already approved in a number of African countries so legalisation shouldn’t be too difficult, but as Dr Wheetman from the LSTM says: “It is warranted to suggest the safety of modified fungus needs to be confirmed for people and livestock.”

The researchers claim they do not want to drive the extinction of mosquitoes but to break the transmission of malaria, but with reports vary from them being an important food source and as a pollinator for plants, others claim they do not occupy an niche in the environment so would a world without mosquitoes really be a bad thing? A fantastic in depth article can be found at Forbes detailing how the loss of mosquitoes may or may not impact their ecosystems.

Optimising a natural system is an elegant way of tackling Malaria especially when insecticide resistance is only likely to get worse, and this research could only be the beginning of leveraging fungal biotechnology to our advantage. Similar research found that Metarhizium could be used to inhibit Plasmodium development in already infected mosquitoes, so what could be next?

Read the full article published in Science on 31st May here

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