Zika virus: from mosquito bites to locating centrosomes?

Since the beginning of this year, pregnant women are advised not to travel to Brazil or a long list of other Central and South American countries. The reason is a dramatic increase in the number of Brazilian newborns with microcephaly.

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Microcephaly, which literally means ‘small head’, is a disorder that stems from a wide variety of conditions that reduce brain growth. Children born with microcephaly have brains that are smaller in size but similar in structure compared to healthy people. All people with microcephaly have intellectual disabilities and some have seizures or motor problems. Recent research on cases of microcephaly caused by the Zika virus suggests these babies might have additional specific abnormalities, see here.

Most cases of microcephaly are caused by gene mutations, however given the dramatic increase in microcephaly cases, something else must currently be going on in Brazil.

The rise in babies born with microcephaly in Brazil has been accompanied by a high prevalence of the Zika virus, which is transmitted through mosquito bites. Zika virus RNA has been detected both in the mothers and the amniotic fluid of Brazilian embryos with microcephaly. These two facts together have caused doctors and regulators to suspect that the Zika virus causes microcephaly.

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In this post I will discuss what the Zika virus is and how a simple mosquito bite can lead to the development of microcephaly in a baby.

The Zika virus, which was first discovered in monkeys in 1947 (Dick, 1952), is part of the Flaviviridae family, which also includes Dengue and West Nile Virus. In contrast to its siblings, infection with the Zika virus does not lead to any serious symptoms, only sometimes causing some fever, headaches and joint pains, never lasting longer than a couple days.

However, recently something seems to have changed in the Zika virus. Not only is there a 20-fold increase in Bazilian babies with microcephaly, there also appears to be a rise in adults with the Gauillain-Barré syndrome, which is an autoimmune disorder affecting the nervous system.

One possibility is that the virus has become more effective in crossing the border between our blood and our brain (see here), usually one of the toughest borders to cross (see blood brain barrier). It has been proven before that the Zika virus has the capability to cross over from the blood into the brain. In 1952 researchers injected Zika virus into the stomachs of mice and subsequently found traces of the virus in their brains (Dick, 1952). Another study, in 1971, showed that when injected directly into the brain, the virus is able to proliferate and infect both neurons and glia cells (Bell, 1971).

So, we know that the virus can travel to the brain and infect brain cells, and that it might have improved its ability to do so recently. But what does it do once it's there?

When the Zika virus arrives in a cell, it starts to affect the process of autophagy. Autophagy literally means ‘eating oneself’. All cells in our body ‘eat’ or recycle molecules that have grown old or are working incorrectly. Many viruses, including the Zika virus, can hijack this process and use it to reproduce themselves (Hamel et al., 2015. How they do this exactly is unclear, but it probably involves firstly preventing themselves to be ‘eaten’ by the cell, and secondly using this process to recruit the perfect mixture of lipids and other building blocks to mass reproduce themselves.

Is this the link between Zika and microcephaly? Does eating up the wrong molecules increase cell death, leading to fewer brains cells and thus smaller brains? Although this seems like a plausible hypothesis, it does not seem to be the case. Rather, Zika hijacking the autophagy process appears to distort a completely different process in neurons: the process of cell division.

Most, if not all, cases of microcephaly have been linked to problems in cell division. During development, neural tissue undergoes a delicate sequence of cell divisions.

Although a full explanation of this process would require its own post, it can roughly be split up in two types of cell divisions: symmetrical cell divisions and asymmetrical cell divisions. During a symmetrical division a neural stem cell divides into two neural stem cells. In an asymmetrical division a neural stem cell divides into a neural stem cell and a daughter cell that is further down the path towards neuronal or glial commitment and that is usually limited in how many more times it can divide itself.

Figure from Berika et al., 2014. Frontiers in Cell and Developmental Biology.

Figure from Berika et al., 2014. Frontiers in Cell and Developmental Biology.

In people with microcephaly, this balance has probably been shifted to the side of asymmetrical divisions (Thornton & Woods, 2009). And just a small shift can make a huge difference. For example, if a neural stem cell makes 10 asymmetrical divisions, it has made 10 committed daughter cells. On the other hand, 10 symmetrical divisions could lead to more than 500 committed daughter cells!

So what determines if a cell will make an asymmetrical or symmetrical division? One crucial factor appears to be the alignment of the centrosomes compared to the surroundings of the cell (Thornton & Woods, 2009). And this alignment is influenced by many factors, INCLUDING factors that are also involved in autophagy (Tetro, 2015)!

It thus seems like the mechanism Zika uses to hijack the autophagy process also messes with cell division of neural stem cells. And so, if Zika ends up in a developing baby, the neural stem cells of this baby may make too many asymmetrical divisions, leading to fewer neurons and thus a smaller brain.

Of course, this is still just a hypothesis. Although several studies have shown a link between factors influencing autophagy and centrosomal alignment, no one has yet proved that the Zika virus influences centrosomal alignment. Actually, we don’t even know if it is the Zika virus that causes microcephaly. The mosquito carrying the Zika virus could also be carrying another disease that causes the microcephaly. More research will hopefully soon help us understand what is affecting pregnant women in Brazil and how we can treat them.

Further reading: Review about the link between microcephaly and the Zika virus: http://www.sciencedirect.com/science/article/pii/S1286457916000083 Review about centrosomal alignment and microcephaly: http://www.sciencedirect.com/science/article/pii/S016895250900184X

References

  • Bell, T.M.., Field, E.J., Narang, H.K. (1971). Zika vrus infection of the central nervous system of mice. Arch Gesamte Virusforsch, 35, 183-193.
  • Dick, G.W (1952). Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg, 46 521–534
  • Tetro, J.A. (2015). Zika and microcephaly: Causation, correlation or coincidence? Microbes and infection, doi:10.1016/j.micinf.2015.12.010
  • Thornton, G.K., Woods, C.G. (2009). Primary microcephaly: do all roads lead to Rome? Trends in Genetics, 25(11), 501-510.