Discovered a biomarker that detects hemorrhagic dengue

Discovered a biomarker that detects hemorrhagic dengue https://i1.wp.com/www.eresviral.com/wp-content/uploads/2018/11/Descubierto-un-biomarcador-que-detecta-el-dengue-hemorrágico.jpg?fit=212%2C146&ssl=1

Discovered a biomarker that detects hemorrhagic dengue







Patients infected with the dengue virus can count in the near future with blood tests with which it will be possible to verify if the disease can evolve towards its most lethal type: hemorrhagic dengue. In addition to the classic symptoms of fever and pains propagated by the body, the hemorrhagic outcome of the disease causes bleeding in small vessels of the skin and other organs.



In the framework of a study conducted in Brazil by researchers from the Faculty of Pharmaceutical Sciences and the Institute of Biology of the University of Campinas (Unicamp), and the Faculty of Medicine of São José do Rio Preto (Famerp) -with the support of the Support Foundation for Scientific Research of the State of São Paulo - FAPESP identified lipids that function as biological markers of hemorrhagic dengue. To this end, the authors verified the action of more than 4,000 molecules in human plasma by mass spectrometry.



The researchers elucidated the determinant role of phosphotidylcholine, which is the most common phospholipid in human tissues, in the imbalance of the coagulation cascade - the process whose objective is to stop bleeding through the action of molecules such as platelets. and fibrinogen and blood clot formation, which results in hemorrhagic dengue.



In an article published in the journal Scientific Reports, the group describes the evolution of the disease in the plasma of 20 patients suffering from hemorrhagic dengue and treated at the Base Hospital, linked to Famerp. This study also had a control group, conformed with the blood plasma of 10 healthy patients and not infected with the dengue virus.



"We were able to detect for the first time that the dengue virus helps in phosphorylation [el agregado de grupos fosfato a las proteínas]. This is how it causes an increase in the phosphotidylcholines in the blood and a natural imbalance in the path of coagulation. These lipids act against coagulation and, therefore, cause hemorrhagic fever, "said Rodrigo Ramos Catharino, a professor at the Faculty of Pharmaceutical Sciences of Unicamp and one of the authors of the article.







Dengue transmitter insect. (Photo: James Gathanay, CDC (CC0))



This study is the result of the doctorate of Carlos Fernando Odir Rodrigues Melo, who counted on it with a FAPESP scholarship and with the direction of Ramos Catharino.



The imbalance of the coagulation cascade can happen for other reasons: due to hemophilia, for example. "But we do not know if the intermediary molecules of these other processes are the same as in cases of hemorrhagic dengue. They can be molecules other than lipids that we observed in our study, specific markers produced by the dengue virus, "said Ramos Catharino.



By analyzing the plasma of the patients, the group was able to monitor the evolution of dengue towards hemorrhagic fever, which allowed to understand the mechanism of the disease. According to this study, the lipid alterations in the cells infected by the dengue virus become evident when the virus takes control of the cellular metabolism, modulating the mechanisms of autophagy. [la degradación de las estructuras del medio intracelular] to contemplate the needs of viral replication.



The scientists also managed to observe the performance of intermediary molecules, such as diacidiglycerol (DAG) and inositol triphosphate (IP3). According to the hypothesis, the main impact on the evolution of the disease towards hemorrhagic fever would be in the action of the virus in phosphorylation, especially in kinases -proteins whose function is to form a phosphate derivative based on other proteins-, which causes an imbalance in the coagulation.



"We managed to track the mechanism of development of the disease in the plasma of patients and identify markers of evolution precisely when there is a decrease in platelets in the blood. Therefore, the increase in phosphotidylcholine is an indicator that there will be hemorrhagic fever. There is a large balance of the coagulation cascade that is altered by the virus from its action on several intermediary molecules (lipids) so that the coagulation does not occur, "said Ramos Catharino.



Apart from identifying biomarkers for hemorrhagic dengue and enabling the disease to be detected by means of blood tests in the future, this study also allowed us to arrive at a greater understanding of the mechanism of action of the dengue virus in hemorrhagic fever.



Although the structure and composition of the dengue virus (and its four serotypes) have been widely studied, the phenotype of the infection and the action of small molecules, such as lipids, have not been clearly determined yet.



Dengue is an acute disease of rapid evolution that generates fever and pains in the body. According to the World Health Organization (WHO), this disease affects around 390 million people in the world annually. A small amount of dengue cases can evolve into hemorrhagic fever, which is much more lethal. These cases, although the reason for this is not known, correspond to children and people infected more than once with serotypes of the dengue virus.



"It is known that the sooner hemorrhagic fever is detected, the better the patient's chances of survival. But since it is still not possible to know how the disease will evolve, it is very common for patients whose symptoms progress to hemorrhagic fever to be sent home before their situation worsens, "he said.



According to the researchers, the discovery of the mechanism that leads to hemorrhagic fever can have an impact on the development of new treatments and vaccines.



"Our main objective is to develop the tests that indicate the existence of hemorrhagic dengue and also to better characterize the disease process. Does it take three, four or more days to manifest? Not even that we know for sure. Another interesting line is to correlate with vaccines this mechanism that we discovered. One of the difficulties of immunization today has to do precisely with hemorrhagic dengue, "said Ramos Catharino.



According to what was recorded in the scientific literature, the outcome of dengue virus infection depends on several factors related to the onset of viral infection: viral load, the presence of non-neutralizing antibodies, the recruitment of cells and the production of immune mediators.



"These factors determine whether the environment is favorable or unfavorable for the progression of the disease, by controlling the viral infection or damaging the inflammatory reaction associated with vascular permeability. However, the lack of reliable and other metabolic markers for protective or pathological responses was an important gap that hindered the development of new diagnostic tests or possible vaccines, "say the researchers in the article. (Source: AGENCIA FAPESP / DICYT)

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