Virus factories and hijacked proteins: How could Zika cause microcephaly?

There’s something missing from all the coverage of Zika virus, the mosquito-borne flavivirus that’s spread across 26 countries in the Americas since May 2015. While Zika usually doesn’t cause symptoms in adults, the outbreak coincided with a 20- to 40-fold surge in babies born with microcephaly—a very small head and an increased risk for mental retardation. With good reason, scientists are working hard to better understand and develop a vaccine against this esoteric virus.

But the scientist in me wants to know: Just how could Zika cause microcephaly?

Microcephaly has lots of causes, from genetic problems to alcohol exposure to congenital infections with syphilis bacteria, rubella virus, and Toxoplasma parasites. Microbes can cause birth defects indirectly—like by triggering fever in a pregnant woman—and directly, if the microbe crosses the placenta. Recent case reports have found that Zika virus can slip through the placenta and into the developing fetal brain.

Thanks to several recent case reports, we have a big-picture idea what Zika can do once it’s in the brain. Among infected fetuses and newborns, major brain structures were shrunken or even missing. The eyes and the optic nerves were damaged and shriveled. The remaining nervous tissue had fewer neurons than normal and was studded with immune cell nodules and calcium deposits—signs of inflammation and cell death.

To get an idea how Zika causes inflammation and death, we have to turn to studies in mice and cultured human skin cells. A 1971 study in mice found that the virus penetrated the brain’s neuron and glial cells, forming clot-like structures that the scientists called “virus factories.” These clots were microscopic evidence of the virus hijacking autophagy, the cell’s process for breaking down unwanted garbage proteins. A 2014 study using infected human skin cell cultures found that, like its other flavivirus cousins, Zika steals components needed for autophagy and uses them to replicate itself. Between a hijacked garbage system and microscopic factories churning out millions of viruses, it’s no wonder that cells are dying and the immune system is reacting.

However, a recent letter to the editor of Microbes and Infection proposes an interesting hypothesis for how a hijacked garbage system could lead to microcephaly. In his letter, Canadian microbiologist Jason Tetro proposes that Zika may actually be causing microcephaly by interfering with a cell’s centrosomes—structures important to evenly dividing chromosomes between two dividing cells. Some proteins are involved both in autophagy and in stabilizing these centrosomes. When Zika hijacks autophagy to replicate itself, it may be co-opting these double-duty proteins. Without the proteins, the chromosomes are less likely to be divided equally—leading to the sorts of genetic problems and chromosome abnormalities that most often cause microcephaly.

As for why we’re not seeing even more babies born with microcephaly: The severity of these effects probably relates to how developed the fetus is when it’s infected. Infections early in the pregnancy often have worse effects, because the brain and major organs are just being formed. Later infection usually has subtler effects.

Personally, I’m wondering about these fetuses infected later with Zika. Are we going to see a surge in kids with subtler problems, such as learning disabilities, that won’t be detected until they start school? Or will we be able to get a vaccine out there fast enough that Zika will become another contained tragedy, like thalidomide?

Reference:

Tetro JA (2016). Zika and microcephaly: causation, correlation, or coincidence? Microbes and infection / Institut Pasteur PMID: 26774330

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