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An enzyme found in a bright shrimp helps researchers test drugs blocking malaria transmission.
Scientists from the University of São Paulo (USP) have created a transgenic parasite and introduced into their DNA the genetic sequence responsible for the production of nanoluciferase, a protein produced commercially by the American biotechnology company Promega from the substance extracted from the crustacean.
In the laboratory, the transgenic microorganism is brought into contact with the drug to be tested. If it is ineffective, that is, unable to prevent the transmission of the disease, nanoluciferase emits light.
Initially, 400 substances were tested, nine of which proved effective against the malaria parasite. They would work as a kind of "cure" of the mosquito. In other words, they would eliminate the ability of the insect to transmit the disease.
The life cycle of the malaria parasite
To understand how the test works, you need to know a little about the life cycle of Plasmodium, the protozoan responsible for malaria.
According to researcher Daniel Youssef Bargieri of the Institute of Biomedical Sciences (ICB) of the University of São Paulo (USP), responsible for the team that created the transgenic microorganism, malaria is caused in man by at least five species of Plasmodium. about one hundred are known to infect other primates, birds, reptiles and various mammals.
"In our lab we used as a model study Plasmodium berghei, which infects mice and not people," he explains.
According to Bargieri, the life cycle of the microorganism is complex. "It multiplies in the blood, inside the red blood cells.It is this proliferation that causes the disease we call malaria," he says.
During the process, however, certain parasites in the blood can become gametocytes, a sexual phase (ie, in men and women) in which the protozoan ceases to multiply.
In this phase, if the infected individual is stung by a mosquito of the genus Anopheles, which is the Plasmodium transmitter, the protozoan will restart the cycle by infecting another host.
More effective drugs to prevent the transmission of the disease
Today, there are drugs that treat malaria in humans very effectively. In a few days, the patient is cured. These drugs work against forms of the parasite that multiply in the blood (those that cause the disease).
"The treatment is not very effective against gametocytes," says Bargieri.
"That is, the person is cured, but continues to carry the forms of the microorganism that are transmitted to the mosquito, which means that even after treatment, it can be a source of transmission."
As a result, the researcher and his group decided to create a model to test drugs that could prevent this from happening.
"For this, we created the transgenic parasite that produces nanoluciferase only when there is zygote formation," says the researcher.
Thus, it emits light when the gametocytes turn into gametes and they fertilize to form a zygote – which means that the substance tested is not effective against transmission.
He says the experiment was done in very small wells of laboratory plates – each one has 96, but there are others with 384 and 1,536 wells. In each of them is put a different medicine.
"Next, we place the gametocytes in the wells under conditions that they think are in the mosquito, that is to say in a culture medium that mimics the conditions found by the parasite in the mosquito. "insect organism," says Bargieri.
"Fertilization takes place and after six hours we could measure the amount of light emitted.If there is emission, it is because fertilization has occurred, otherwise it is not to test thousands of medicines simultaneously, looking for those that prevent light emission, ie those that avoid fertilization. "
The resistance of the parasite leads to the search for new drugs
Although there are several effective remedies for the treatment of malaria, there is still a rush of new ones because, over time, the parasite develops resistance to them.
"In addition, currently available drugs are not very effective against the microorganism forms transmitted to the vector mosquito.There is interest in the development of drugs or vaccines capable of blocking transmission."
Of four of the nine promising drugs, the ability to prevent malaria transmission was unknown. In addition to the 400 initials, the USP group has already tested another 9,000 people.
"We are now evaluating the results and defining the ones that are most promising so that they can be tested in other models of parasites infecting humans," Bargieri said.
"These tests are done initially by offering blood infected by a mosquito," he says.
"If the substances we found are effective at blocking the insect infection (blocking the transmission), the next step would be to test it clinically."
In addition, the experiment also validated the method of screening substances.
Those with potential for transmission will be included in a group of drugs considered as potentially antimalarial and acting at different stages of parasite development.
The idea is that those who block the transmission are associated with current drugs, so that the person returns home cured and without transmitting the disease.
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