Naturally Occurring Delftia tsuruhatensis and Its Secreted Harmane Show Promise in Blocking Malaria Transmission

Over the past century, malaria control interventions have changed little. Insecticides remain the primary means of preventing malaria, but as mosquitoes and Plasmodium continue to adapt and develop resistance, innovative and novel approaches are needed.

In a new study, Dr. Marcelo Jacobs-Lorena, an honorary professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, and his colleagues, in collaboration with researchers from GSK's Global Health Drug Discovery unit, confirmed that a naturally occurring bacterium and a chemical it secretes can inhibit the development of malaria parasites in mosquitoes, meaning the mosquitoes are unable to transmit the parasites to humans. This method has clear advantages: it is low-tech, easy to replicate, and does not use genetic modification technology. It can also work perfectly alongside existing effective control strategies. The relevant research findings were published in the August 4, 2023, issue of the journal *Science*, with the paper titled “Delftia tsuruhatensis TC1 symbiont suppresses malaria transmission by anopheline mosquitoes.”

How was this project launched?

This new research began in the laboratories of GlaxoSmithKline (GSK) in Spain, where scientists were studying malaria drugs. To test these drugs, they regularly infected mosquitoes with a type of malaria parasite called Plasmodium falciparum. Over time, they were no longer able to infect the mosquitoes. They searched for possible reasons and found that a bacterium called Delftia was present in all screened mosquito samples.Delftia tsuruhatensis) strain (they named the strain Tres Cantos 1, abbreviated as TC1).

Preliminary tests showed that if these mosquitoes carry TC1, their development would be affected. To further the research, they contacted Jacobs-Lorena for collaboration and then sent this bacterium to Jacobs-Lorena.

How to verify this theory?

First, these authors fed TC1 bacteria to mosquitoes in their laboratory, confirming that this bacterium inhibited the development of Plasmodium parasites within the mosquitoes. Next, Wei Huang, the first author of the paper and a senior research associate in the Jacobs-Lorena lab, discovered that if the bacteria were cultured and the supernatant (the liquid part of the culture medium excluding cells) was used to feed mosquitoes, the development of Plasmodium parasites inside the mosquitoes would also be suppressed. This indicates that the supernatant contains inhibitors, which the bacteria secrete to attack the Plasmodium parasites.

At this point, GlaxoSmithKline PLC. commissioned Spain's Fundación MEDINA to fractionate [separate the mixture into its components] this supernatant to identify the inhibitor, and then send each fraction back to the Jacobs-Lorena team, which mixed each fraction with malaria-infected blood to feed mosquitoes for testing. Using this method, the team determined which fraction contained the inhibitor.

Identification of Antibacterial Compounds Through Bioassay-Guided Fractionation of Supernatants from In Vitro Cultures of Delftia. Image courtesy of Science, 2023, doi:10.1126/science.adf8141。

Ultimately, scientists at Fundación MEDINA identified the inhibitory compound as harmane. It turns out that harmane can be easily purchased from chemical companies. The Jacobs-Lorena team ordered this compound and confirmed its inhibitory effect on the malaria parasite.

Subsequently, Wei came up with a different testing idea: he dried harmaline on a glass plate, allowed mosquitoes to rest on the plate for an hour, and then fed the mosquitoes blood infected with Plasmodium. He found that the development of Plasmodium in mosquitoes resting on harmaline was severely affected, indicating that harmaline can penetrate the mosquitoes' cuticle (the outer layer of the mosquito's legs) and inhibit Plasmodium development.

What are the benefits of these findings for malaria control measures?

Jacobs-Lorena believes it is necessary to view the issue in the right perspective. For a full century, malaria control has been achieved by killing mosquitoes with insecticides. Using this bacterium to turn mosquitoes into "non-transmitters" represents a new approach to malaria prevention and control. Another significant finding is that once mosquitoes acquire this bacterium, it will remain with them for life.

How to implement it in the field?

Many studies use sugar baits—a mixture of sugar, mosquito attractants, and insecticides—deployed in the field to kill mosquitoes. One suggestion proposed by these authors is to mix the sugar bait not with insecticides but with bacteria, allowing mosquitoes to feed on it. The advantage of this approach is that extensive experiments using sugar baits are already being conducted in the field, making this technique well-refined. Preliminary implementation trials in Burkina Faso have yielded promising results, confirming the potential of this intervention for malaria control. Another possibility is to spray harmine on mosquito nets or walls.

Can the use of this bacterium effectively reduce the number of deaths from malaria?

The modeling study described in this paper suggests that if this approach is combined with the distribution of long-lasting insecticide-treated bed nets and other measures, it can further reduce clinical malaria cases by 15%. In other words, more lives can be saved.

But it is necessary to make this clear: malaria cannot be eliminated by this method alone. A multi-pronged approach, including insecticides, vaccines, and drug treatments, is absolutely essential. All available control measures must be combined.

The Practical Significance of These Findings

The mostJacobs-LorenaThe exciting reality of using a new strategy to prevent and control malaria is drawing near. Keep in mind that in Africa, a child dies from malaria every minute. Moreover, this bacterium has not been genetically modified.

Some laboratories are developing genetically modified mosquitoes that, through the use of gene drives, can kill the malaria parasite. A gene drive is a method that spreads genes suppressing the malaria parasite within mosquito populations. However, releasing these genetically modified mosquitoes into the wild presents significant challenges in terms of regulatory approval and acceptance by local communities.

Jacobs-Lorena pointed out that Delftia is a type of natural bacteria initially isolated from mosquitoes, and it is widely present in nature. This means that, compared with other methods using genetically modified mosquitoes or bacteria, it can be tested in the wild in a shorter time. (Bioon.com)

References:

1. Wei Huang et al. Delftia tsuruhatensis TC1 symbiont suppresses malaria transmission by anopheline mosquitoes. Science, 2023, doi:10.1126/science.adf8141.

2. Malaria’s Latest Foe? Bacteria.
https://publichealth.jhu.edu/2023/bacteria-a-new-weapon-against-malaria