Mechanism affecting the multiplication of the dengue virus lineage is discovered

Janaína Simões | Agência FAPESP – One strain of dengue virus 1 in Brazil may override another, although it is less common in mosquitoes carrying the virus and in infected human cells. The discovery was made in collaborative research supported by FAPESP and developed by several national institutions and a university in the United States.

According to research, the lineage activates less the immune system response of patients. Less combated, the virus can multiply in the human body, increasing the chances that the person is bitten by a mosquito and infects others.

Researchers studied strains 1 and 6 (L1 and L6) of the type 1 dengue virus that affect the population of São Paulo, José do Rio Preto, in the interior of São Paulo. The study showed that although L1 has a greater ability to multiply in mosquitoes and cells, L6 can minimize and even disable the immune responses of the human body, making this line occupy the L1 site.

three practices to study the multiplication of the dengue virus and to explain why one strain has exceeded another. Our research has uncovered a new phenomenon that explains how a virus survives in a population, "said Maurício Lacerda Nogueira, badociate professor of the Virology Research Laboratory at the Department of Dermatological, Infectious and Parasitic Diseases of the School of Medicine. Medicine of São José do Preto. (Famerp) and one of the authors of an article published recently in PLOS Neglected Tropical Diseases with the results of the research.

"But not only observe if the virus multiplies more or less in the mosquito or in the human cell to understand why one lineage takes the place of another.We need to know how the virus interacts with the virus. be human as a whole, "said Nogueira, also president of the Brazilian Society of Virology, to Agência FAPESP

The study brings new fundamental knowledge for the production of vaccines in the fight against the disease. . "Understanding globally how the virus interacts with people helps us understand how vaccines work and is fundamental for us to understand," he said.

In Brazil, there were three introductions of dengue virus type 1: strains 1, 3 and 6, all of the same genotype. In São José do Rio Preto, L6 traffic was initially observed at least since 2008. In 2010, L1 was identified for the first time in the city. For a period, both circulated together.

L1 was expected to have a greater ability to propagate in transmissible cells and mosquitoes, Aedes aegypti, since it arrived after L6 and was able to bind. However, from 2013, L1 began to decline until it was no longer detected in the population, contrary to the expectation that the new lineage would replace L6.

This fact contradicted the scientific knowledge produced regarding the prevalence of a lineage. (19659004) It may occur if the line introduced into the medium multiplies better in human cells than that already in the environment. The other hypothesis is that the line that arrived later multiplies more in the mosquito. In both cases, it is said that the virus that has supplanted the other has a better viral form.

Epidemiological Physical Condition

A third explanation emerged from a study conducted in Puerto Rico in 2015, where it was found a strain of dengue virus with a worse viral form than those already in the world. 39 environment, but that eventually outweighed the others. It has been found that this lineage inhibits the interferon system, a protein that induces an antiviral response whenever someone is infected with viruses, which decreases their replication. In this case, the process is called epidemiological aptitude.

In the case of Brazil, none of this has happened. First, the researchers sequenced the genomes of the two strains of virus. They have 47 different amino acids, they are genetically distant, but they have competed with each other and the L6 has won.

"The information we had up to here said that the L6 had to multiply better, so have prevailed, but when we look we saw that L1 multiplies 10 times more, on average, than L6 If L1 did not do this in human cells, the hypothesis was that the best viral form would explain why L6 would multiply better in the mosquito. Orally captive mosquitoes – bred for scientific experiments: To feed, the mosquitoes stabbed a membrane containing mouse blood contaminated with dengue viruses of lines 1 and 6. "Again, L1 has multiplied 10 times better in the mosquito than L6, "he said, the possibility that mosquitoes in captivity are not representative of those found in the environment.In a new experiment, where mosquito eggs were collected in the env Irritated and hatched in the laboratory, the same result was achieved: L1 was even more effective at multiplication than L6, although studies have shown that patients infected with L6 had a much higher viral load than L1 [19659004] The hypothesis of epidemiological fitness remained, as in Puerto Rico, where it was discovered that a dengue virus encoded interferon-inhibiting RNA. The interference in the Brazilian case has not been confirmed. "We realized that we were facing another mechanism, different from the three already known," Nogueira said.

To solve the mystery, researchers began to study the immunological aspects of the virus's interaction with the immune response. Using computer prediction systems, they found that L1 was able to activate the B and T cells that make up the immune system much more than L6

Then, in studies involving mice and cells given by Of people infected with the virus, scientists were able to stimulate and measure the activation of B and T lymphocyte responses, noting that L6 activated a weaker response than L1. They also measured the level of cytokines present in the serum taken from patients. "In general, we observe that L1 multiplies much better, but also strongly activates the immune system, both human and mouse, that is to say, L1 induces a very large response from the body L6, however, multiplies less, but either inhibits or does not stimulate or sparingly stimulates immune system responses, so the body takes longer to recognize the virus, "he said.

With this, the amount of virus in line 6 in humans is on average 10 times higher than that of 1, the researchers found. They also observed that the lineage 1 virus multiplies much more in the mosquito and that it has a much larger local replication when it infects the person.

Except that this replication induces a strong activation of B and T lymphocytes, resulting in the increase of cytokines, it generates a strong immune response, able to inhibit the systemic replication of the virus in the body. As a result, the viral load is lower, which reduces the spread to mosquitoes, that is, fewer people will be infected.

In the case of the lineage 6 virus, despite its lower capacity for multiplication in the mosquito. initial replication after biting a person, it produces a weak activation of B and T lymphocytes and stimulates the production of cytokines that inhibit the immune response rather than stimulate it

"With this, there is a replication. much larger person, namely a greater amount of virus in the population, which is able to infect more mosquitoes.We conclude that L6 has a better epidemiological condition than L1, which, in turn, has a better viral fitness than L6, "said Nogueira.

The study lasted two and a half years and involved a group of 24 (UFRJ) and Minas Gerais (UFMG), Unesp and a foreign collaborator – Nikos Vasilakis, a researcher at the Center for Tropical Diseases of the United States. University of Texas (Galveston), "Using epidemiological, phylogenetic, molecular and immunological badyzes, the authors of the research have demonstrated that differences in host immune response determine the dynamics of dengue circulation. in two circulating strains in the city, suggesting that the factors that influence the dynamics of dengue transmission are much more complex than previously thought, "Vasilakis said.

Article Viral Immunog (doi: https://doi.org/10.1371/journal.pntd.0006525), by Tauyne Menegaldo Pinheiro, Mauricio Lacerda Nogueira and others, is available on http://journals.plos.org / plosntds / article? id = 10.1371% 2Fjournal.pntd.0006525.