Zika virus: what it is and how it works.

 

 

 

 

 

 

 

 

 

 

The beginning of the Olympics games 2016 in Rio have been clouded by the risk of Zika virus (ZIKV) infection that is scaring Latin America since the beginning of 2015. Although ZIKV was identified for the first time already in 1940s, the Brazilian outbreak is the largest one described so far, leading the World Health Organization to declare it a world emergency at the beginning of 2016.

 

What is Zika virus?

Zika is a Flavivirus, the same family of dengue or yellow fever viruses. ZIKV is a RNA-virus, which means that its genome is a molecule of RNA. The RNA can be directly translated into proteins. In order to duplicate, the virus has to synthesize a complementary molecule of RNA that will be the template for the synthesis of the new RNA molecule for the newly generated virus.

Although the virus is mostly transmitted after bites of infected mosquitoes, a growing number of evidence has also shown transmission between people, through blood, human tissues and cells, and from pregnant Zika-infected mothers to their fetuses.

 

Consequences of ZIKV infection. Although some studies report cases of serious neurological complications in the adult, such as Guillain-Barre´ syndrome (a disease causing progressive paralysis), the infection normally causes only mild symptoms such as fever, headache, arthralgia (pain of joint), myalgia (muscle pain), and rash on the skin. In some cases it can even be asymptomatic.

 

However, the main concern arises from ZIKV infections in fetuses. Indeed, in fetuses, the infection has been linked to severe microcephaly, which means an abnormal brain size of the fetus. In the beginning of 2016, the New England Journal of Medicine reported the case of a 25-years old woman living in Brazil that, after the first trimester of pregnancy, showed typical symptoms of ZIKV infection, and abnormalities in fetus development, like microcephaly.

 

What do we know about the cellular mechanism? An important step ahead in uncovering the mechanism of action of this virus comes from a study of an american group showing the effect of a particular strain of the virus at a single cell level.

The virus infects human skin cells, and indeed the mosquito bite is the major route of infection, and it has also been found in amniotic fluids (fluid that surrounds the fetus during pregnancy in order to protect it) of two women whose fetuses showed symptoms of microcephaly, suggesting a viral infection of placenta (a structure temporarily present during pregnancy that acts as a barrier, regulating the exchanges between the mother and the fetus, in order to filter the toxic microorganism and avoid their way to the fetus). Finally, ZKV was found in the abnormally small (microcephalic) brain of fetuses.

Although the virus also infects other cell types (skin cells, fibroblasts, astrocytes), researchers have shown that HEK293 cells -a cell line commonly used in biology labs, deriving from kidney- show low infection of ZIKV. Finding the effects of the virus only in the brain of fetuses, and the broad infection of  human neural progenitor cells (hNPCs, cells that can be differentiated into cortical neurons) supports a strong preference of the virus for neuronal cells (neurotrophism).

In vitro, low doses of ZKV were sufficient to infect about 90% of hNPCs in three days, and 30% of the infected cells were dead. In vivo, microcephalic fetal brain showed some deposits, called “calcifications” that might represent destroyed neuronal structures, which probably caused the arrest of development after the 3^rd month of gestation. A more accurate analysis investigated on the effects of ZKV infection on gene expression of the infected cell: the infection caused 1) a down-regulation of genes related to the cell cycle (the different stages that a cell undergoes during its life), and 2) an up-regulation of the genes that control the apoptosis (Apoptosis is the “cell death pathway” that a cell starts when something wrong is going on. We can call it a “cell suicide”). All these results together explain microcephaly, as the NPCs are the main cell types constituting a developing embryonic brain, and their survival and normal development are strongly impaired in ZKV infected cells.

After infection, the virus replicates in these cells. Indeed, particles resembling the structures required for virus replication are found in microcephalic brains and in cultures of hNPCs neurons. Once collected from cell cultures, these particles have the ability to infect other cells.

 

The vaccine. The concern of virus propagation for human health has led several labs to collaborate and work on the virus, and a couple of months ago the first vaccine against Zika virus has been developed and tested in mice.

The authors tested two types of vaccine showing that both of them are effective in preventing Zika infection in mice, with only one shot: the DNA-vaccine and the purified inactivated virus vaccine.

In the first case, the DNA of some parts of the virus genome are introduced in the cells. These parts of the genome normally code for viral proteins (which means that are translated into proteins). Once expressed in mouse cells, the cell uses the DNA to produce these few viral proteins and expresses them on the cell surface. These proteins stimulate the immune system of the receiving animal, making it produce many antibodies. The vaccine will not be infective per se as it has only few proteins of the virus (not all the elements of the virus required for the infection), but it will instruct the cells, which means that it will give the cells all the information to know how to react in case they enter in contact with the virus.

In the second case, the parts of the virus that are infective are destroyed by a specific treatment (with chemical agents, or heat,…) in order to render the virus inactive and unable to infect the receiving cells, that will be anyway ready to respond in case of contact with the virus.

 

We are sure far from knowing everything about Zika virus, but the parallel studies from different labs all over the world contributed to provide us many information about it, and now we already know a lot about the symptoms of the infection, the action mechanism, and we have very encouraging data for a human vaccine in the next future. It feels good to know that the biomedical research of the past two centuries (at least) gave us so many tools to face these things.

 

References: 

Zika Virus Associated with Microcephaly. Mlakar et al. New England Journal of Medicine, 2016.

Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Tange et al. Cell Stem cell, 2016.

Vaccine protection against Zika virus from Brazil. Larocca et al. Nature 2016.