Professors’ research helps create treatments for Zika

Researchers at the Keck School of Medicine of USC have identified two protein molecules that may be responsible for the harmful effects of the Zika virus on unborn children.

The findings, which were published in the scientific journal “Cell Stem Cell” on Aug. 11, may lead to the development of a vaccine preventing these proteins from inhibiting fetal brain formation. The researchers received support from the Hastings Foundation, Fletcher Jones Foundation, Global Research Lab Program, National Research Foundation of Korea, Alzheimer’s Association and the Cure for Alzheimer’s Fund.

In the past year, Zika cases have increased exponentially in South and Central America, leading to greater awareness of the illness and its effects. The virus, transmitted by mosquito bites and, in some cases, sexual activity, oftentimes produces no severe or long-lasting symptoms. In fact, about 80 percent of infected individuals do not experience any symptoms, according to Jae Jung, a professor and chair of the Department of Molecular Microbiology and Immunology at Keck. Instead, the virus proves most dangerous when it infects pregnant mothers, causing microcephaly in their newborns.

“Pregnancy is a different case than regular healthy individuals,” Jung said. “We don’t know exactly why, but pregnant women are sometimes highly susceptible to some viral infections such as Zika. Surprisingly, the Zika virus crosses the placenta and infects the fetus and ultimately blocks fetal brain development.”

The two proteins, NS4A and NS4B, have caused microcephaly in thousands of infants born from Zika-infected mothers. This collaborative endeavor between the virology and neurobiology disciplines is the first to examine Zika virus on a molecular level, with researchers analyzing human neural stem cells from second-trimester fetuses.

“Cells that are determined to produce nerve cells that are called neural stem cells. These cells, when infected with Zika virus, stop proliferating,” said Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at Keck. “They are also unable to position themselves in the nervous system during the development process. Fetuses are affected more than adults because they depend completely on growth whereas adults already have formed brains.”

Jung and his team of researchers came to the conclusion that NS4A and NS4B proteins are the ones that result in the formation of unusually small brains by studying three strains of Zika in second trimester human fetal neural stem cells. They found that these microcephaly-causing proteins obstruct the Akt-mTOR pathway, which is responsible for autophagy, or the recycling of pathogens. Blocking the pathway allows Zika and other viruses to multiply. As a result of the energy Zika virus is using to proliferate, the neuronal stem cells are left with metabolic deficits, thereby severely inhibiting their ability to mature into neurons and other brain cell types.

Moreover, the study found that when these proteins, NS4A and NS4B, interfere with fetal neural stem cells, the size of brain organoids was cut in half. The proteins also inhibited the growth of fetal neural stem cells by 65 percent, and the ability of these stem cells to mature into brain cells was reduced by up to 51 percent. These decreases manifest in infants as microcephaly, a condition that severely limits cognition and overall health.

Moving forward, the USC researchers will test the function of NS4A and NS4B proteins in mouse models and brain organoids.

“A vaccine is already under development,” said Zhen Zao, an assistant professor of research physiology and biophysics in an email to the Daily Trojan. “However, therapeutic antibodies targeting Zika NS4A and 4B proteins may also work.”