From source of infection to technological pioneer, can scientists really turn mosquitoes into "anti-malaria assistants"?

Mosquitoes have always been regarded as one of the most troublesome insects in human history. Their bites not only cause annoying itching, but more seriously, they are the main vectors of many deadly diseases. So far, more than 300 mosquito-borne viruses have been found in the world, including malaria, yellow fever, dengue fever and Zika virus. These diseases pose a huge threat to global public health, and people are terrified of mosquitoes. In fact, if the deaths caused by the diseases they spread are also counted, mosquitoes are undoubtedly the most murderous animals in the world.

However, scientists at Leiden University in the Netherlands have recently made a breakthrough: by innovatively genetically modifying malarial parasites, mosquitoes can carry modified malarial parasites to vaccinate humans. The success of this technology may transform mosquitoes from disgusting "public enemies of mankind" to "anti-malaria helpers" that protect health. What is going on? Let's talk about it below.

Can mosquitoes “vaccinate” humans?

Malaria is an infectious disease caused by Plasmodium, which is mainly transmitted to humans through the bites of infected Anopheles mosquitoes. Malaria is mainly prevalent in tropical and subtropical regions, especially in Africa and Southeast Asia, with a high incidence rate. Although there are currently two approved malaria vaccines, malaria still infects about 250 million people each year, causing about 600,000 deaths worldwide, and is one of the major challenges facing global public health.

Artemisinin combination therapy, which combines artemisinin with other antimalarial drugs, is the recommended treatment for malignant and severe malaria. In 2015, Chinese scientist Tu Youyou won the Nobel Prize in Physiology or Medicine for discovering artemisinin. Source: Xinhua News Agency

How do malarial parasites enter the human body through mosquitoes? When a common female Anopheles mosquito carrying malarial parasites bites a human, the malarial parasite larvae are injected into the human blood with the mosquito's saliva. After the malarial parasites mature in the human body for 7 to 14 days, they enter the red blood cells and multiply rapidly, causing the red blood cells to rupture. When the red blood cells rupture, a new generation of malarial parasites is released into the blood, continuing to infect more red blood cells, forming a vicious cycle that may even cause death.

In contrast, the genetically engineered "improved version of Plasmodium" GA2 will stop further development about 6 days after infecting the human body. It will not cause red blood cells to rupture, nor will it cause the vaccine recipient to develop malaria, but it can effectively stimulate an immune response, thereby exerting a protective effect similar to that of a vaccine.

To test whether exposure to parasites can help humans become immune to malaria, the researchers conducted a small-scale clinical trial. In the experiment, participants in the experimental group were first bitten by mosquitoes carrying the "modified version of Plasmodium" GA2, and then three weeks later they were exposed to mosquitoes carrying ordinary Plasmodium. The results showed that 89% of participants bitten by GA2 mosquitoes did not contract the disease after contacting mosquitoes carrying Plasmodium, which is higher than the two currently approved malaria vaccines (protection rate is about 75%), and also higher than the modified Plasmodium GA1, which stops developing 24 hours after infecting the human body (about 13%).

Although the preliminary results are encouraging, the current clinical trial scale only involves 20 people before it can be widely used. Therefore, the safety and effectiveness of the mosquito vaccine need further verification, and there is still a long way to go before it can be widely used.

Using mosquitoes to fight mosquitoes?

This is not the first time scientists have taken action against mosquitoes to prevent and control infectious diseases transmitted by mosquitoes.

As early as 2010, Professor Xi Zhiyong's team from the Joint Research Center for Tropical Vector Control of Sun Yat-sen University and Michigan State University injected a modified endosymbiotic bacterium, Wolbachia, into Aedes mosquitoes, successfully blocking the mosquito's ability to spread the dengue virus.

Dengue fever is a disease transmitted by Aedes mosquitoes. After being infected with the dengue virus, patients may experience symptoms such as high fever, headache, and joint pain. In severe cases, they may develop hemorrhagic fever or shock syndrome, which are life-threatening. Currently, there is still no specific antiviral drug that can directly treat dengue fever.

The study found that after Wolbachia was injected, it could inhibit the replication and spread of dengue virus in the Aedes aegypti mosquito, the main vector of dengue fever, thereby preventing the spread of the virus. In addition, the immune characteristics of Wolbachia can be passed on to the offspring of mosquitoes, further reducing the risk of mosquitoes spreading dengue fever. Later, Professor Xi Zhiyong's team further expanded this method to the prevention and treatment of diseases such as malaria and Zika virus, creating a new idea for mosquito immune regulation.

Field locations, release schedule, and larval suppression by HC male releases Source: Reference [6]

In 2016, with the approval of the Ministry of Agriculture, Professor Xi's team began to release "sterilized male mosquitoes" injected with triple Wolbachia on a large scale in residential areas of two isolated river islands in Guangzhou. These "sterilized male mosquitoes" cannot lay eggs after mating with wild female mosquitoes, resulting in the inability of the population to reproduce.

By maintaining a dominant ratio for a certain period of time, the wild mosquito population was finally suppressed, achieving the effect of controlling or even eradicating disease-transmitting mosquito species. In two years, the team released millions of "sterilized male mosquitoes" and successfully eliminated the wild Aedes albopictus population in the two residential areas. With the continuous development of technology, the scope of release has gradually expanded to many cities in Guangdong.

Researchers are releasing "sterilized male mosquitoes" Source: Guangzhou Daily

Take mosquitoes as teachers?

In addition to preventing and controlling infectious diseases, scientists have also drawn a lot of inspiration from mosquitoes for bionic technology.

You may be curious, why mosquitoes feel almost no pain when sucking blood, but injections are so painful? This is because the average length of the mosquito's mouthparts is only 1.5 mm, and the diameter is less than 0.1 mm, which is almost imperceptible. The diameter of the common syringe needle is usually between 0.45 and 0.7 mm, which is at least four times thicker than the mosquito's mouthparts.

Scanning electron microscope image of a mosquito mouthparts, showing elements of the maxilla and labrum. Source: Reference [4]

How can such a tiny mouthpart easily pierce our skin? Through microscopic observation, scientists have discovered that the mosquito's mouthparts are composed of multiple parts, including the upper lip, lower lip, tongue, upper jaw and lower jaw. When a mosquito sucks blood, the first thing it attacks is the upper jaw, which pierces the skin like a sharp needle; then, the lower jaw has serrations that repeatedly cut the skin to help the mouthparts penetrate deeper. The upper and lower jaws of the mosquito will repeatedly pierce and cut at a frequency of 10 to 15 times per second, looking for suitable capillaries. When the mosquito finds a suitable blood vessel, the tongue begins to inject saliva to prevent blood clotting and anesthetize the skin to reduce pain. Finally, the upper lip is responsible for inserting into the blood vessel and starting to suck blood.

Inspired by the mosquito mouthparts, scientists at Temple University in the United States designed a bionic surgical needle. By testing it with polyvinyl chloride gel, they found that this specially structured needle is more efficient than ordinary needles. Compared with traditional needles, the serrated needle reduces the resistance by about 60% when penetrating the gel, while reducing the area of ​​tissue deformation by about 36%. If the vibration mode of the mosquito mouthparts is imitated, the friction resistance can be further reduced by about 10%.

3D printed mosquito-inspired needle Image source: Reference [4]

In addition, in 2023, the research team of the Shanghai Institute of Microsystem and Information Technology of the Chinese Academy of Sciences was also inspired by the structure of mosquito mouthparts and developed a bionic flexible neural probe. The probe can penetrate the dura mater and achieve minimally invasive implantation in multiple brain regions. It can also sense the presence of intracranial blood vessels during implantation and provide early warning of damage. This further demonstrates the broad application prospects of bionic design in the field of medical devices.

From genetically engineered Plasmodium and Wolbachia biological control strategies to the application of bionic technology, scientists have not only effectively suppressed the ability of mosquitoes to spread diseases through innovative means, but also drawn many valuable inspirations from the biological mechanisms of mosquitoes, promoting the progress of medicine and engineering technology. In the future, mosquitoes may become an important "bridge" to promote public health and scientific and technological innovation.

References

[1] Yin Qikai, Fu Shihong, Wang Huanyu, Liang Guodong. Current status and prospects of mosquito-borne arboviruses and mosquito-borne arboviral diseases in my country. Chinese Journal of Tropical Medicine. 2024, 24(4): 478-485 https://doi.org/10.13604/j.cnki.46-1064/r.2024.04.21

[2] Lamers OAC, Franke-Fayard BMD, Koopman JPR, et al. Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite[J]. New England Journal of Medicine, 2024, 391(20): 1913-1923.

[3] Kudiabor H. This malaria vaccine is delivered by a mosquito bite[J]. Nature.

[4] Gidde STR, Islam S, Kim A, et al. Experimental study of mosquito-inspired needle to minimize insertion force and tissue deformation[J]. Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine, 2023, 237(1): 113-123.

[5] Singh B, Ahmad KA, Murugaiah M, et al. Quasi-steady aerodynamic modeling and dynamic stability of mosquito-inspired flapping wing pico aerial vehicle[J]. Frontiers in Robotics and AI, 2024, 11.

[6] Zheng X, Zhang D, Li Y, et al. Incompatible and sterile insect techniques combined eliminate mosquitoes[J]. Nature, 2019, 572(7767): 56-61.

[7] Bian G, Xu Y, Lu P, et al. The endosymbiotic bacterium Wolbachia induces resistance to dengue virus in Aedes aegypti[J]. PLoS pathogens, 2010, 6(4): e1000833.

[8] Bian G, Joshi D, Dong Y, et al. Wolbachia invades Anopheles stephensi populations and induces refractoriness to Plasmodium infection[J]. Science, 2013, 340(6133): 748-751.

Planning and production

Author: Denovo Team

Reviewer: Wang Duoquan, Researcher, Institute of Parasitic Diseases Control and Prevention (National Center for Tropical Diseases Research), Chinese Center for Disease Control and Prevention

Meng Fengxia, researcher at the Institute of Infectious Diseases, Chinese Center for Disease Control and Prevention

Planning丨Ding Zong

Editor: Ding Zong

Proofread by Xu Lai and Lin Lin