Researchers identify molecular mechanisms associated with Zika microcephaly

Researchers from the State University of Campinas (Unicamp), the D’Or Institute for Research and Teaching and the Federal University of Rio de Janeiro (UFRJ) have identified molecular processes that may be associated with microcephaly in babies whose mothers were infected with the Zika virus.

The discovery proposes a model, at the molecular level, for understanding the set of sequelae caused by infection during pregnancy and opens the way for new therapeutic targets to be developed.

The study, published in the journal Molecular Neurobiology analyzed changes in the expression of proteins in infected cells (proteomics) and found that, by invading the developing brain of babies, the Zika virus modulates energy production and also controls the metabolism of RNA expressed in the cell nucleus.

According to the proposed model, these alterations would interfere, above all, in the maturation of oligodendrocyte predecessor particles, neural cells responsible for the production of myelin, a lipid substance essential for the exchange of information between neurons.

“With the analysis of protein expression, it is assumed that oligodendrocytes appear less mature, which can lead to deficits in the formation of the myelin sheath, with very bad consequences for the brain of developing babies”, says Daniel Martins-de- Souza, professor at the Institute of Biology at the State University of Campinas (IB-Unicamp) and coordinator of the research.

The study was supported by Fapesp (Fundação de Amparo à Pesquisa do Estado de São Paulo) through a postdoctoral fellowship granted by Juliana Minardi Nascimento, first author of the article, and a master’s grant by Danielle Gouvêa Junqueira.

“Usually, when any virus infects a cell, it aims to dominate it so that it can multiply freely and then advance to other parts of the host organism. In the case of the Brazilian Zika lineage, by specifically invading neuronal cells, instead of If there is a greater change in the expression of proteins linked to these classic purposes, we observe a greater change in proteins associated with metabolism”, explains Martins-de-Souza.

To reach these conclusions, the researchers performed two different types of experiments. First, they infected human neural stem cells with the Brazilian lineage of the Zika virus to identify the change in protein expression. Human neural stem cells were obtained from induced pluripotent stem cells, that is, skin cells reprogrammed to generate neural stem cells.

After the study with stem cells, the researchers used infected neurospheres (organ developed in vitro that simulates the morphology and functioning of part of the brain) to observe what can happen during neurodevelopment.

To compare the results, the researchers repeated the experiments with neural stem cells and neurospheres infected by the dengue virus and the African lineage of the Zika virus – normally, both do not infect brain cells, let alone cause cases of microcephaly.

“These experiments carried out with the dengue virus and the African lineage of the Zika virus do not reflect what happens in nature. This is because these viruses do not cross the blood-brain barrier, which protects the brain from invading pathogens. However, these tests served to compare proteomic analysis and also to understand what Brazilian Zika triggers in neural cells”, explains Martins-de-Souza.

“In the experiments carried out on neural stem cells, the Brazilian zika presented a very different behavior from the other two viruses. modulated this very important part of neuronal development, acting on the differentiation of neurons and glial cells [astrócitos, micróglias e oligodendrócitos]”, it says.

In the neurospheres, the performance was also diverse. “Once again, the Brazilian Zika strain modulates cellular metabolism and also controls RNA metabolism [que está sendo expresso no núcleo das células infectadas]important factors to explain microcephaly”, he pointed out.

bare wire

Martins-de-Souza explains that the action of the virus in overactivating or inhibiting the expression of proteins linked to metabolism has several effects. In the case of the Brazilian lineage, the alteration caused deficits in the maturation of neural cells important for the babies’ brain development.

This is because a family of proteins called hnRNP (heterogeneous nuclear ribonucleoproteins) and linked to cellular metabolism was one that underwent changes in expression.

“They are very important in the maturation and development of oligodendrocytes and, consequently, in the production of the myelin sheath. Thus, Brazilian Zika seems to interfere in this process that can lead to myelination deficits even before the formation of neuronal cells in the period fetus”, says Martins-de-Souza.

The researcher uses the metaphor of electrical wires to explain the importance of the myelin sheath in the functioning of the brain. “The myelin sheath would be a kind of covering for the wires of the brain”, he compares.

It is worth remembering that neurons connect both chemically and through electrical impulses. “In the brain, the myelin sheath would be a kind of protection for the axons [parte dos neurônios que transmite impulsos elétricos, as sinapses]. When there is not even the production of oligodendrocytes so that there is the myelin sheath ‘covering’ the neurons, this energy is lost”, he says.

Martins-de-Souza emphasizes that oligodendrocytes are cells that are already present in the neurodevelopment of babies inside the mother’s uterus, with an important role for brain development.

“Although oligodendrocytes do not perform the task of promoting the myelin sheath anytime soon, [isso acontece apenas nos primeiros anos de vida do bebê], they have the function of maintaining the energy metabolism of neurons. When this very important process of formation does not occur satisfactorily, we have important changes in neurodevelopment, leading, in the case of the Brazilian lineage of the zika virus, to microcephaly”, he says.