Tropical virusVirology

Dissecting the replication complex of the Dengue virus to identify new therapeutic targets

Affiliations: Paris University, France

Journal reference: https://doi.org/10.1016/j.celrep.2017.11.094

Summary: In this article, Hafirassou et al. identify new cellular factors crucial for Dengue virus infection. These could serve as a starting point for the development of novel therapeutic approaches against the virus.

Dengue is a tropical virus caused by a tiger mosquito bite

Dengue virus (DENV) is a tropical and subtropical virus transmitted to humans by the tiger mosquito Aedes aegypti. It belongs to a family of viruses called flavivirus that are transmitted by blood-sucking insects and that cause diseases such as Zika or Yellow Fever. DENV is the most common zoonosis (disease transmitted from animals to humans) with 390 million infections per year, among which 96 million present symptoms. In most cases, the virus only causes mild symptoms such as a flu-like syndrome, but severe forms can occur and lead to death.

A new tiger mosquito is causing Dengue in Europe and across the globe

At present, there is no curative treatment or vaccine against dengue and care is limited to combating the symptoms until the patient recovers. This virus is worrisome because an estimated 3.9 billion people live in a risk area, a number that is likely to increase in the future due to environmental factors and the globalization of transport. As a matter of fact, another tiger mosquito also able to transmit DENV and called Aedes albopicpus is gradually colonizing Europe. Research to find new approaches to fight DENV is therefore a major public health issue.

DENV entirely depends on its host in which it operates through a “replication complex”

Like all viruses, DENV is an obligate intracellular parasite. This means that the virus is entirely dependent on its host cells in which it diverts cellular factors to its advantage at every stage of its viral life cycle.

After entering the cell, DENV releases its genome at the endoplasmic reticulum (the part of the cell where proteins are produced) and usurps cellular ribosomes (the machinery that produces proteins) for its use. The viral proteins in collaboration with other cellular factors induce vesicle-like structures that represent a suitable place for genome amplification (making multiple copies of the virus). More precisely, these vesicles host the “replication-complex” that concentrates vital elements for the virus, and that protects the newly synthesized viral genomes from the host’s immune system. Consequently, identifying the cellular components of the replication complex is an excellent way to find new therapeutic targets.

In this paper, the authors identified 279 proteins in the replication complex, 58 of which seem crucial to the DENV

To identify the proteins of interest, Hafirassou et al. successfully isolated the DENV replication complex and determined its composition with an analytical technique called mass spectrometry. With this approach, the authors identified 270 cellular proteins in the replication complex.

In order to determine which proteins are important for the virus, the authors further performed an siRNA screen. With this approach, the authors identified 58 proteins that seem crucial to the DENV. Indeed inhibiting these proteins decreased the viral infection.

Among the 58 proteins, the authors further pinpointed the role of a protein complex called “OST”

Hafirassou et al. showed that among these proteins, RACK1 protein and the OST complex proteins were involved in the viral replication stage. In addition, they discovered that the role of the OST complex in infection was mediated by a process called glycosylation. Furthermore, the authors demonstrated that blocking the glycosylation function of the OST complex by using a small drug inhibitor named NGI-1 prevented the infection of the cells by DENV. This proof of concept study paves the way for developing a new generation of host-targeting agents for the treatment of dengue infection.

Take home message: a potential target for new treatments against DENV

Tropical diseases risk is growing to be a more important public health issue with time due to global warming. Dengue fever caused by the DENV is the most important among them in terms of numbers of contaminations. Moreover to date, there are no therapeutic or preventive treatments. In order to provide reflection on this subject, Hafirassou et al. have for the first time, identified the cellular proteins involved in the viral genome amplification, a crucial stage in viral replication and spread. Their work has identified proteins like RACK1 and the OST complex proteins that play a crucial role during DENV infection.

While RACK1 protein should be further investigated in order to understand its role in infection, Hafirassou et al. reported that the OST complex is involved in the glycosylation of viral proteins, an important modification essential for their function. The authors further showed that blocking the glycosylation function of the OST complex using a drug called NGI-1 prevented infection of the cells. This finding indicated that the OST complex could be a potential target for developing new therapeutic options against dengue infection.

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