DDX3 protein would be key in the process: They seek to decipher how the respiratory syncytial virus replicates to advance new therapeutic targets

The research led by Professor Mónica Acevedo, PhD in Microbiology and academic in the Virology Program of the Institute of Biomedical Sciences of the Faculty of Medicine, aims to better understand how RSV replicates when it infects the host, in order to lay the foundations for new therapeutic targets. Project seeks to know how the respiratory syncytial virus replicates to advance in new therapeutic targets regular fondecyt project.

Cecilia Valenzuela León, Journalist University of Chile.- This is how the researcher explains it, pointing out that although this mechanism has already been studied in viruses such as Human Immunodeficiency, in syncytial it is very little known. “The concept of “unwinding” the replicative cycle is based on the fact that we will study the DDX3 protein, which is a helicase; that is, an enzyme that participates in the process of unwinding structures of the RNA molecule. We started this project when we saw that this helicase colocalizes within what are called inclusion bodies; that is, it is in the same position as abnormal subcellular structures formed as a result of viral infection, which frequently correspond to the places where the replication of components of the viral particle takes place: they are like viral factories inside the cell”.

The project focuses on understanding the metabolism of viral RNA: “when the virus replicates, it forms genomic RNA and messenger RNA to produce proteins; DDX3 could possibly have an action on both, always focused on these cellular structures that are the inclusion bodies. The idea is to try to decipher this mechanism, because we have seen that when we inhibit the catalytic activity of DDX3 the inclusion bodies change, either in number or size, compared to a cell in which this intervention was not made. We don’t know if the virus is capturing the protein or the protein enters to inhibit viral replication as a cell protection mechanism; that is what we want to understand.”

With the aim of finding a possible therapeutic target?

It is always difficult to inhibit a protein in a cell, because they all fulfill specific functions, but it has been seen that DDX3 has a function that is dispensable to the cell; For this reason, it has been described as a possible target that can be used against many viral infections.. In fact, it is an essential cofactor in HIV replication and progress is being made in the design of drugs directed against this enzyme.

To do this, the team of researchers -also made up of the doctors Lorena Tapia, Ricardo Soto-Rifo and Fernando Valiente, also from the ICBM Virology Program-, will work on an organoid model of the upper respiratory epithelium: “We are going to do this in collaboration with a researcher at the Texas Children’s Hospital, Dr. Pedro Piedra, with the aim of learning this technique there and then bringing it back. It is based on the fact that a respiratory sample is obtained from, for example, a pediatric patient, who is the one who is most affected by RSV, and it is cultured in order to obtain different cell types, and even have cilia. Thus, everything that we describe at the cellular level we will be able to see if it can eventually be similar or not in this generated organoid. in vitro”, adds Professor Acevedo.

And it is that these Organoids “are a three-dimensional cell culture. It is a platform that is being used a lot, in particular to avoid using the animal model, which is also complex and requires high levels of biosafety for its implementation”. In addition, he adds that as a future projection “organoids could be generated to study individual characteristics of certain patients; for example, of those that worsen more, to see why that happens in certain hosts”.

Will the results obtained be extrapolated to all RSV variants or strains?

We don’t know, it’s one of the things we’ll describe. In addition, we will study this mechanism in a virus very close to RSV, which is the metapneumovirus, which is increasingly common; we want to see if this mechanism is conserved.