Thursday, May 12, 2016

Zika virus microcephaly mechanisms

A few weeks ago, Dr. James Bale saw a series of MRI images in a medical journal of MRI scans of babies infected with Zika in the womb.

They scans showed something Bale had seen only a few times in his 30-year career: a phenomenon called fetal brain disruption sequence.

As the fetus's brain starts to grow, it creates pressure, which pushes on the skull and causes it to grow. But if something stops brain growth — such as a virus — pressure on the skull drops. And the skull can collapse down onto the brain.

The skin around the head continues to grow, Bale says. So the baby is born with wrinkles of skin at the back of the neck and a tiny skull. In some cases, the baby's head is as small as an orange, or about half the size of a healthy baby's head.

"It's quite remarkable what the Zika virus is doing to the brain of young infants," Bale says. "Many of them will die often in infancy, and the majority, if not all, will then have a long-term, severe developmental problems."

Now scientists think they have an understanding about how Zika causes these severe brain malformations. The findings come from a series of mouse experiments, published Wednesday in three leading journals.

In one study, published in Nature, Alysson Muotri and his team at the University of California, San Diego, infected pregnant mice with Zika and looked to see how the virus harmed the baby mice.

"We detected the virus all over the mice and in different regions of the body," Muotri says.

But for some reason — and scientists don't know why yet — Zika is particularly attracted to brain cells. And once inside the cells, Muotri says, Zika turns them into viral factories that start producing huge amounts of virus. Until they burst.

"They explode, and more viral particles are released that can infect other cells. And they can just amplify themselves," Muotri says.

More and more brain cells get infected. More die. This cell death is already a problem for the fetus. It scars the brain and creates inflammation.

But the situation gets worse because the brain cells infected by Zika are extremely special. They're called neural progenitor cells. And they're responsible for building a large portion of the brain.

"These are fast-replicating cells that will give rise to billions of cells in our brains," Muotri says.

So if a fetus loses even just a small percentage of these cells, a portion of its brain will never develop. "And the impact later in life would be dramatic," he says.

A second study, published in the journal Cell Stem Cell[see], confirmed that Zika destroys neural progenitor cells inside a growing embryo. In that experiment, a team of scientists at the Chinese Academy of Sciences, injected the virus directly into the brains of mice embryos, developing inside their moms.

Muortri says death of brain cells is likely the major way that Zika causes microcephaly in babies. But it isn't the full picture.

In the third study, Indira Mysorekar and her colleagues at Washington University in St. Louis, also infected pregnant mice with Zika.

They found the virus not only damages the brain but also attacks the placenta.

"The nutrient and blood exchange that normally happens between the mother and the fetus is reduced," Mysorekar says. This slows down the baby's growth — and may hurt the brain as well.

Mysorekar and her colleagues published their findings in the journal Cell.

She says mouse experiments can never tell us exactly what's happening in people. Human anatomy is more complicated.

But one thing is clear: Once Zika infects the fetus, "it leaves a lot of havoc and devastation in its wake," she says. "It's almost like a tornado or an earthquake. There is death following Zika."


  1. Fernanda R. Cugola, Isabella R. Fernandes, Fabiele B. Russo, Beatriz C. Freitas, João L. M. Dias, Katia P. Guimarães, Cecília Benazzato, Nathalia Almeida, Graciela C. Pignatari, Sarah Romero, Carolina M. Polonio, Isabela Cunha, Carla L. Freitas, Wesley N. Brandão, Cristiano Rossato, David G. Andrade, Daniele de P. Faria, Alexandre T. Garcez, Carlos A. Buchpigel, Carla T. Braconi, Erica Mendes, Amadou A. Sall, Paolo M. de A. Zanotto, Jean Pierre S. Peron, Alysson R. Muotri et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. Published online 11 May 2016.

    Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain–Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKVBR) strain causes birth defects remains absent6. Here we demonstrate that ZIKVBR infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKVBR crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKVBR outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKVBR in human neurodevelopment.

  2. Jonathan J. Miner, Bin Cao, Jennifer Govero, Amber M. Smith, Estefania Fernandez, Omar H. Cabrera, Charise Garber, Michelle Noll, Robyn S. Klein, Kevin K. Noguchi, Indira U. Mysorekar, Michael S. Diamond. Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell. Published online.

    Zika virus (ZIKV) infection in pregnant women causes intrauterine growth restriction, spontaneous abortion, and microcephaly. Here, we describe two mouse models of placental and fetal disease associated with in utero transmission of ZIKV. Female mice lacking type I interferon signaling (Ifnar1−/−) crossed to wild-type (WT) males produced heterozygous fetuses resembling the immune status of human fetuses. Maternal inoculation at embryonic day 6.5 (E6.5) or E7.5 resulted in fetal demise that was associated with ZIKV infection of the placenta and fetal brain. We identified ZIKV within trophoblasts of the maternal and fetal placenta, consistent with a trans-placental infection route. Antibody blockade of Ifnar1 signaling in WT pregnant mice enhanced ZIKV trans-placental infection although it did not result in fetal death. These models will facilitate the study of ZIKV pathogenesis, in utero transmission, and testing of therapies and vaccines to prevent congenital malformations.

    •Establishment of an in utero transmission model of ZIKV infection
    •ZIKV infects placental cells and results in intrauterine growth restriction
    •ZIKV infection and injury of the fetal brain is observed
    •ZIKV infection of fetuses can occur by a trans-placental route