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Zika could be a factor in more pregnancies
Three of the fetuses were born with small heads, but not quite so small they would be diagnosed with microcephaly — the most striking and widely discussed result of Zika infection since Brazilian doctors raised the alarm in 2014 of babies with arrested brain development.
"That is very high — 100 percent exposure — of the virus to the fetus along with inflammation and tissue injury, in an animal model mirroring infection in human pregnancies quite closely. It's sobering. If microcephaly is the tip of the iceberg for babies infected in pregnancy, the rest of the iceberg may be bigger than we've imagined."
The UW-Madison researchers, along with collaborators at Duke University and the University of California, Davis, published their study of the Zika-infected pregnancies today in the journal PLOS Pathogens. The work was funded by the National Institutes of Health. Each pregnancy was followed from point of infection in the first or third trimester, assessing maternal infection and fetal development at regular intervals, and examining the extent of infection in the fetus in each pregnancy when term was reached.
Although the new study did not find abnormal brain development, researchers did discover unusual inflammation in fetal retinas and optic nerves, if infected during the first trimester.
"Our eyes are basically part of our central nervous system. The optic nerve grows right out from the fetal brain during pregnancy. So it makes some sense to see this damage in monkeys and human pregnancy — problems such as chorioretinal atrophy or microphthalmia, in which the whole eye or parts of the eye just don't grow to the expected size."
The similarities between monkey pregnancies and reported complications in Zika-affected human pregnancies further establish Zika infection in monkeys as a way to study the progression of the infection and associated health problems in people. "There are so many things about Zika infection we can't study as well in pregnant humans — or fast enough to make a difference for a lot of people who may be infected," adds Dawn Dudley, UW-Madison pathology research scientist and one of the lead authors of the new research along with Antony and obstetrics and gynecology graduate student Sydney Nguyen. An animal model opens the door to studying how Zika infection interacts with other infections (like dengue virus), how the effects of early pregnancy infection might be different from later infection, and, according to Dudley, whether quick treatment with some antiviral therapies could manage the damage of what has come to be known as congenital Zika syndrome.
"The precise pathway that the virus takes from mom's bloodstream to the fetal bloodstream, across that interface, cannot be studied except in an animal model."
Golos' research group found damage from Zika infection in every part of the interface between mother and fetus — the placenta, amniotic fluid in the womb and the lining of uterus. While the immediate effects may not be as dramatic as microcephaly, "the results we're seeing in monkey pregnancies make us think that, as they grow, more human babies might develop Zika-related disease pathology than is currently appreciated," Golos adds.
""We're tantalizingly close to generating bona fide human blood stem cells in a dish.This work is the culmination of over 20 years of striving."
In the second step, they added genetic regulatory molecules (called transcription factors) to push the hemogenic endothelial cells into their blood-forming state. Starting with 26 factors identified as possible candidates, they eventually came to five (RUNX1, ERG, LCOR, HOXA5 and HOXA9) that were both needed and in sufficient amounts to create blood stem cells. The factors were delivered via a lentivirus, into the cells.
Finally, the genetically engineered hemogenic endothelial cells were transplanted into mice. Weeks later, a small number of the animals carried multiple types of human blood cells in their bone marrow and circulating blood. Some of the mice began to mount a human immune response after being vaccinated.
ES cells and iPS cells were similar in creating blood stem and progenitor cells with the technique. But researchers are more interested in iPS cells, which add the ability to derive cells directly from patients and the disease being modeled.
The technique now produces a mixture of blood stem cells and hematopoietic progenitor cells, that also give rise to blood cells. But the ultimate goal is to expand their ability to make blood stem cells in a way that's practical and safe, without the need for a viral delivery or transcription factors. Next, the team wants to introduce gene-editing techniques like CRISPR to correct genetic defects in the pluripotent stem cells before converting them to full blood cells.
One challenge in making bona-fide human blood stem cells is that no one's been able to fully characterize all the elements of these cells as yet.