How a mosquito fights a virus

Mosquitoes have strong defense mechanisms against viruses such as dengue and Zika. Yet, millions of people still become infected with these viral diseases via mosquitoes every year. PhD candidate Joep Joosten of the Radboudumc investigated how the defense of mosquitoes against viruses works. On 19 November, he will defend his thesis on the so-called piRNA molecules that play an important role in the immune system. His work provides fundamental knowledge that may lead to new approaches to combat these viruses.

In recent years, we have seen occasional small outbreaks of the viral disease dengue in southern Europe, which had not occurred there in previous decades. This happened during hot and wet summers, which tropical mosquitoes love. The habitat of these mosquitoes is slowly expanding, and therefore also the distribution of the viruses that are spread by these mosquitos. Thus, in addition to dengue, also Zika and chikungunya are becoming more common. This is due to global warming, but also because people are traveling more and are living more closely together in large cities.

Blood meal

Mosquitoes bite people because they need a blood meal for the production of their eggs. The blood can contain viruses, so-called arboviruses. These viruses must multiply in the mosquito, before they can be injected into a human at the next bite. What happens to the virus in mosquitoes? What determines whether a mosquito can transmit a virus? That is what the research group of virologist Ronald van Rij has been studying for years.

His PhD candidate Joep Joosten looked very closely at how mosquitoes fight viruses. "Thanks to their good defenses, the mosquitoes are not bothered by the viruses," Joosten explains. "If you knock out that defense, mosquitoes infected with a virus will die sooner. Apparently a balance has evolved in evolution: enough virus particles are produced for further spread of the virus, but not so many that it makes the mosquito sick. That would hinder transmission to humans, because a dead mosquito no longer bites. During my PhD research, I described a mechanism involved in the immune response of mosquitoes to arboviruses, such as Zika and dengue." 

Alarm bells

The defense mechanisms of mosquitoes against viruses are largely based on small RNA molecules. RNA is best known as a messenger in the cell. The blueprint for the building blocks of a cell, proteins, lies in the DNA. When a building block is needed, the code for that one building block is copied from the DNA to an RNA molecule. That RNA is translated into a protein by the protein factories in the cell.

The genetic material of mosquito-borne viruses also consists of RNA. It is therefore very difficult for a cell to distinguish virus RNA from its own RNA. Joosten: "Yet there are differences. Cellular RNA molecules, for example, almost always consist of a single strand. The genetic material of arboviruses also consists of a single strand, but when viruses multiply they temporarily form a double-stranded RNA molecule. An animal or human cell recognizes a double-stranded RNA molecule as foreign and sets off all the alarm bells."

Tiger mosquito

It was already known that the mosquito possesses a sophisticated system for degrading double-stranded RNA. Now a second system has been found that recognizes viral RNA in the mosquito. Joosten has mapped out this system.  He characterized proteins involved in the process by switching them off one by one and investigating the consequences. He found a number of new proteins, with sounding names like Veneno, Pasilla, Atari, Zucchini and Nibbler. These play a role in breaking down virus RNA into smaller pieces, the piRNAs. These, in turn, can recognize and break down other viral RNA, which further strengthens the defense. 

"In-depth knowledge about the mosquito's immune system is important for our understanding of virus transmission and can help us fight viruses," says Ronald van Rij. "Why do tropical arboviruses spread through the tiger mosquito and the yellow fever mosquito, but not through the mosquitoes we have in the Netherlands? It is possible that the immune system plays a role in this. In addition, if we know exactly how the defense of mosquitoes against viruses works, this offers new starting points for developing methods to prevent the spread of arboviruses in the future."

Thesis defense

On 19 November at 12:30 hr Joep Joosten defended his thesis entitled 'Mechanistic insights into the piRNA machinery in Aedes mosquitoes'.

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