"It's a battle, a war. The dengue virus wants to infect the cell. The cell brings out its innate defense system. The virus, its mechanisms to disable that system. They come and go. Only one wins." Andrea Gamarnik is a very measured person, but now he is carried away by happiness and a war jargon on a molecular scale: with his team he has just published a "very important" paper, he said. Specifically, the mechanism by which the dengue virus deactivates the innate antiviral system, which also appears to be different for each serotype.
The latter is perhaps one of the most important findings of the paper published this Monday in the journal of the American Academy of Sciences Proceedings of the National Academy of Sciences (for all, PNAS), whose first author is the researcher Mora González López Ledesma.
As they found, each of the four dengue serotypes deactivates the antiviral resistance of our cells in a specific way, which would explain why even the successful Japanese vaccine of Takeda – whose approval the ANMAT has just specified – does not reflect equally optimal effects against both serotypes.
Thus, the understanding of the strategy of the virus at the molecular level when it tries to bypass the innate cellular defense promises to pave the way for the development of more options (perhaps surpassing) of quadrivalent vaccines, that is, against the four serotypes of dengue, a disease that – we know all too well – transmits the Aedes Aegypti mosquito.
Andrea Gamarnik (left) and Mora González López Ledesma (right) lead the team that made a new finding on dengue. Photo Conicet Instituto Leloir
What is not well known is this other thing that Gamarnik said: that outside of the almost 60 deaths from dengue and the 100,000 infected registered so far in the season that started in July 2022 (the latest national data date back to May 13), "possibly the real infected are already more than one million".
This, taking into account that up to eight out of ten people are asymptomatic, she outlined, and that the underreporting of symptomatic people reaches, as she believes, no less than 50%.
Better dengue vaccines
Returning to the paper, Gamarnik's shock at the finding ("It's really amazing," started the talk with Clarín) has to do with a couple of issues. The first, the twists and turns of his career; Her quest as a scientist.
After her postdoc's return to the United States in 2001 (where she had focused on key pathogens, such as those that cause HIV and hepatitis C, and others that seemed minor at the time: dengue, for example), she focused on mosquito-borne diseases. In Argentina, although the re-emergence of dengue had occurred, the issue weighed little. Gamarnik knows he wasn't wrong.
The second question is linked to the first. A couple of decades passed and, being a senior researcher at Conicet, director of the Molecular Virology laboratory of the Leloir Foundation-Institute and with an achievement for which she will be remembered up her sleeve (having understood -in 2006- how dengue multiplies inside cells), the scientist insisted on the challenge of better understanding the interaction between cell and dengue virus.
Fumigation for dengue in the city of La Plata.
Almost by chance, like an unwanted pearl, his team detected something new about the offensive mechanism of dengue.
Following the chronology, "Covid appeared and all the investigation was interrupted, until not long ago it could be resumed," he said.
Vaccines against the four dengue serotypes
Taking into account that the dengue virus is able to advance against the antiviral mechanisms of mosquitoes and also of humans, and adding to this that "each serotype is practically a virus in itself", it is evident that we are facing a complex pathogen with enormous plasticity.
Precisely, one of the most interesting aspects of the paper concerns this challenge, specifically, the findings regarding the peculiar offensive carried out by each serotype (technically, DEN1, DEN2, and so on). For Gamarnik, this explains, for example, why in available vaccines attenuated viruses type 4 generate greater immunity than type 2 viruses.
"In our work we found that by changing just one amino acid of the NS5 protein of serotype 2 (equivalent to pulling out a brick in the entire building of the viral protein) we can simulate what happens in serotype 4," he said.
In this way, "knowing the changes that could be made at the molecular level so that type 2 does not counteract the action of the immune system, it would be possible, through genetic engineering, to design better vaccines," he encouraged.
Cytokines and protein battle
The moment they studied in the Leloir was the clash of two proteins, one viral and one cellular-human, shock that occurs during infection.
At that time, the dengue protein NS5 deals with trying to limit the production of cytokines generated by the cellular immune response.
The limitation is made by knocking down the prominence of another protein (cellular), called CKD1, in order to appease the release of cytokines. However, they saw in the laboratory, that degradation has its grays according to the dengue serotype.
Without going into more microbiological twists and turns, it is worth remembering the dual function of cytokines; by the way, so mentioned in notes about Covid or regarding the famous Kawasaki Syndrome, in boys.
It is that, just as lymphocytes and other cells are capable of triggering cytokine storms to "fly off the map" to a certain infectious agent, they also sometimes go over the top and generate symptoms that could be somewhat excessive for the patient.
And since all this also happens in severe dengue cases, understanding the subtleties of the serotypes counted so far is key.
In particular, if the objective is to strengthen the organism to give better fight against this type of virus, which, Gamarnik warned, not only carry certain mosquitoes but "also some types of ticks."
The Aedes aegypti, the mosquito that transmits dengue. Photo EFE
In the attempt to strengthen and improve, we are not alone. "Dengue has existed for hundreds of years. It coexists with humans and evolves by selecting mechanisms to deactivate the defense systems of the cell, which is much more stable and changes less," explained the researcher. But it is without annihilating it: "This viral evolution is in pursuit of infecting the host with which the virus coexists."
See also
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