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Dengue Fever Detectives Figure Out Why Mosquitoes Don’t Get Sick

Scientists are forging a path towards a solution to stop the spread of dengue fever and related viruses.

If mosquito-borne viruses make humans so sick, how come mosquitoes don’t get sick themselves? What protects the biters from experiencing any negative effects? Researchers from the Johns Hopkins Bloomberg School of Public Health have figured it out. The team of scientists, led by Dr. Shengzhang Dong, reported in Nature Communications that genetically modifying mosquitoes can sabotage their natural resistance to viruses like dengue and Zika.1

The insect investigators hope that by making mosquitoes vulnerable to the viruses they carry, the infected mosquitoes will become too sick themselves to effectively spread the viruses to humans. 

The global health challenge

Aedes aegypti mosquitoes are efficient disease vectors that transmit viruses (known as arboviruses) of public health concern like yellow fever, dengue virus, chikungunya, and zika virus. Dengue fever infects an estimated 390 million people annually, and around 700,000 deaths are attributed to arbovirus-related illnesses.2

The clever mosquito defense mechanism involves the production of small RNAs (siRNAs) that target and degrade viral RNA to stop viruses from replicating.3 The researchers of the study found that a protein called Argonaute 2 (Ago2) is essential for the siRNA process in Aedes aegypti mosquitoes that reduces viral load of arboviruses to tolerable levels. 

This discovery suggests a new way to fight disease: by manipulating the Ago2 protein and making mosquitoes vulnerable to the viruses they carry, it can potentially kill them and stop diseases from spread.

Why don’t mosquitoes get sick?

Mosquitoes pick up arboviruses by biting an infected person. The virus enters the mosquito’s system and then spreads throughout its body, including the salivary glands. From there, it will be transmitted to another person next time the mosquito bites. But what stops the mosquitos from getting yellow fever or Dengue fever themselves?

When a mosquito is infected with a virus, it creates small pieces of RNA that match the virus’ genetic code. These pieces attach to the viral RNA, and altogether they bind to a key complex with a protein called Argonaute 2 (Ago2), which chews up and destroys the viral RNA keeping their viral load low enough that they are infectious without getting sick themselves.1

Understanding the mosquito defense strategy

Dr. Shengzhang Dong, a senior research associate in the Bloomberg School’s Department of Molecular Microbiology and Immunology, and colleagues, focused on the role of Ago2 in mosquito health. 

The researchers used gene editing technology to remove the Ago2 gene from mosquitoes, creating mutant mosquitoes with no Ago2 protein. They created two different mutant lines: one with a complete loss of Ago2 function and another with only partial loss. Based on the role of Ago2 in the siRNA pathway, they believed that by removing it, they could prevent the mosquitoes from fighting off viruses. 

To test their idea they compared the mutant mosquitoes to normal mosquitoes to see if there were any differences in their overall health and ability to reproduce. They found that while the mutant mosquitoes were similar in weight, blood intake, and egg fertilization, removing the Ago2 gene delayed their larval development, they didn’t lay as many eggs, and they didn’t live as long.

Next, they infected both the mutant and normal mosquitoes with different arboviruses (dengue, Zika, and Mayaro virus). Without the Ago2 gene, mosquitoes lost their ability to fight off the virus. The viruses infected the mosquitoes so severely that they died quickly, before the virus could reach levels high enough to be transmitted or before the mosquitoes could survive long enough to spread it. On the other hand, mosquitoes with the intact Ago2 gene were able to successfully fend off the infection.

How does this help?

Having identified the Ago2 protein’s critical role in protecting mosquitoes from arboviruses, researchers can now focus on using this information to develop new strategies to combat these diseases in humans.

In an ideal world, scientists would genetically modify mosquitoes so that when they become infected with an arbovirus, they can’t resist the symptoms. If inhibiting the Ago2 protein is successful, this approach would cause infected mosquitoes to die rapidly before they could transmit the virus to humans. Importantly, mosquitoes not carrying the virus would remain unharmed, as their Ago2 function would remain intact.

In a press release by the Johns Hopkins Bloomberg School of Public Health, Dr. George Dimopoulos, the study’s senior author, said “The biology of mosquito susceptibility and tolerance to infection is an interesting area of exploration for other pathogens as well. For instance, mosquitoes that transmit malaria parasites could perhaps also be engineered to become sick and succumb to infection.”4

References

  1. Dong S, Dimopoulos G. Aedes aegypti Argonaute 2 controls arbovirus infection and host mortality. Nat Commun. 2023;14(1):5773. Published 2023 Sep 18. doi:10.1038/s41467-023-41370-y
  2. Byaruhanga, Timothy et al. “Arbovirus circulation, epidemiology and spatiotemporal distribution in Uganda.” IJID regions vol. 6 171-176. 3 Feb. 2023, doi:10.1016/j.ijregi.2023.01.013
  3. Karlikow, Margot, Bertsy Goic, and Maria-Carla Saleh. “RNAi and antiviral defense in Drosophila: setting up a systemic immune response.” Developmental & Comparative Immunology 42.1 (2014): 85-92.
  4. “Discovery in Mosquitoes Could Lead to New Strategy against Dengue Fever and Other Mosquito-Borne Viruses.” Johns Hopkins Bloomberg School of Public Health, publichealth.jhu.edu/2023/discovery-in-mosquitoes-could-lead-to-new-strategy-against-dengue-fever-and-other-mosquito-borne-viruses. Accessed 13 May 2024.
Dr Anthony Onunga
Dr Anthony Onunga
Anthony Onunga is a practicing medical doctor with the compulsion to share medical knowledge and concepts to the public in a simple-to-understand manner. He enjoys researching and writing about medical topics and has experience working in the clinical setting. As a science correspondent, Anthony creates content backed with facts and scientific studies. In his spare time, he enjoys watching football, playing chess and exploring new travel destinations.
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