Published in the journal Brain, Behavior, and Immunity elucidates one of the mechanisms whereby zika virus causes neurological complications in adult patients and microcephaly in fetuses. The discovery paves the way for future research to develop drugs that combat the virus.
In the study, which was supported by FAPESP, the researchers found a correlation between the neurological complications caused by zika and high levels of Gas6, a protein that helps the virus invade human cells. They also showed that the main source of Gas6 in such cases is peripheral monocytes, a type of white blood cell that plays a key role in the immune system’s ability to destroy invaders, as well as facilitating healing and repair.
In its active form, Gas6 binds to receptors in the TAM family (Tyro3, Axl and Mer) and, after entering the cell, suppresses the organism’s inflammatory response, facilitating viral replication and aggravating the infection.
The virus itself triggers expression of Gas6, which is augmented in patients with the severe form of the disease. High levels of the protein are associated with an increase in suppressor of cytokine signaling 1 [ SOCS-1 ], a potent inhibitor of type 1 interferon (IFN1). The more potent the mechanism, the worse the prognosis.
José Luiz Proença Modena, a professor at the University of Campinas’s Institute of Biology (IB-UNICAMP) and last author of the article. IFN1 is an important part of the immune response against viruses and other pathogens.
Three groups participated in the study. Modena’s group analyzed blood serum samples from zika patients, including pregnant women. A second group was led by Fábio Trindade Maranhão Costa, also a professor at IB-UNICAMP. Animal trials were conducted by a third group, which was led by Jean Pierre Schatzmann Peron, a professor in the Department of Immunology at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP) and a member of the Scientific Platform Pasteur-USP (SPPU), part of the Institut Pasteur International Network.
Some of the researchers belong to UNICAMP’s Zika Network, established in 2016 after the zika epidemic in Brazil to conduct research that helps deal with the severe impact on public health of the diseases transmitted by the mosquito Aedes aegypti. Singapore’s A*STAR Infectious Diseases Labs also collaborated on the study. The partnership has resulted in other publications, including an article on a study that identified a marker for zika.
Our Zika Network was a precursor of similar collaborations, which continue to take shape and grow. They bring together competent professionals and complementary research lines, combining expertise and know-how. The results are very positive, with collaboration contributing to the quality of the work.
To find out how Gas6 levels correlated with the neurological complications associated with zika, the researchers used the ELISA enzyme-linked immunoassay to analyze serum samples from patients included in a cross-sectional study conducted between February 2016 and June 2017 in hospitals in Campinas, state of São Paulo.
By deciphering this mechanism, we’ve opened up the possibility of further research that could serve as a basis for intervention with drugs. We showed that treatment of cultured cells with warfarin was effective to inhibit multiplication of the virus. We didn’t conduct a clinical trial, but the door is open.
José Luiz Proença ModenaFAPESP, focusing on the immunopathogenesis of COVID-19 in experimental models.