Primate research reveals risks of Zika virus infection during pregnancy

Zika became a household name last year because of the recent outbreak of the virus in the Americas, including several US territories. Since the Berkeley Science Review published an in-depth feature on the subject of Zika last February, researchers have continued to seek the answers to many questions about the biology of the virus and how to control it. Brand-new studies in non-human primate models have revealed that transmission of Zika virus from mother to child during pregnancy is far more efficient than previously known, and that this prenatal infection can inflict subtle developmental abnormalities on the fetus that have not been recognized in clinical studies of humans.

One of the most striking concerns reported during the outbreak was the apparent increased risk of reduced head and brain size (a condition called microcephaly) in babies born to mothers infected with the virus during pregnancy. Microcephaly and other congenital nervous system defects can be caused by other infections, but Zika is the only one that can be spread by mosquitos. Mosquito-borne pathogens are especially dangerous because they are not limited by the normal patterns of contact between humans, and can spread disease in any area in which mosquitos can survive.

In response to the concerns of microcephaly in the 2015 Zika outbreak, the Centers for Disease Control and Prevention (CDC) initiated a screening program for pregnant women and newborns living in US territories where Zika infection rates are high. This allows them to measure the duration and severity of maternal infections, and how these factors correlate with the risk of symptoms in the infants. The initial results of this study were published in a recent Morbidity and Mortality Weekly Report. The data was collected from January 2016 to April 2017 and agreed with previous reports of a 5 percent overall rate of microcephaly and other symptoms (now encompassed by the term “congenital Zika syndrome”) in babies born to mothers with a confirmed Zika virus infection during pregnancy. The rate was not affected by the severity of symptoms experienced by the mother—Zika virus infection is asymptomatic in many cases—but first-trimester infection increased the chances that a child would be born with complications from the virus.

While the quality and volume of clinical data collected about Zika virus has increased in recent years, human patients cannot be subjected to every available test for the virus and associated symptoms. Therefore, it is impossible to rule out other causes for the congenital defects that are observed in the clinic. To make up for these shortfalls, several research groups have studied Zika-related birth defects in macaque monkeys. While macaque research is expensive and labor intensive, human pregnancy and fetal development are much more accurately modeled in non-human primates than in mice or other model organisms. Like humans, primates also experience prolonged Zika virus infection during pregnancy compared to non-pregnant individuals. By studying Zika infection in macaques, researchers can measure the effects of the virus during and after pregnancy in a controlled laboratory setting to rigorously test hypotheses from human clinical data.

In a study recently published from the Wisconsin National Primate Research Center at the University of Wisconsin-Madison, researchers examined the frequency and timing of mother-to-child transmission of Zika virus and the effects of the infection on the fetus. A cohort of four pregnant rhesus macaques was infected with low doses of Zika virus: two during the first trimester and two during the late second to early third trimester. The maternal infection status and fetal growth were closely monitored during the pregnancy, and the mothers and infants were both examined for the presence of Zika virus and tissue abnormalities after a C-section birth.

The first major finding of this study was that Zika virus was transmitted from the mother to the embryo or fetus in all four cases. Despite this highly efficient spread of the virus, the overall effects on the fetuses were mild and the virus was detected in different tissues in each individual. However, abnormalities were found in the eyes of both fetuses infected during the first trimester but not in the fetuses infected during the second to third trimester, perhaps hinting at an increased risk for this axis of congenital Zika syndrome in first trimester infections. Additionally, one of the animals infected in the second to third trimester cleared the Zika virus much faster than the other macaques; despite the reduced duration of virus exposure, Zika was still efficiently passed to the fetus and caused mild abnormalities in several tissues.

The second important result was that the growth of head circumference over time was consistently below average in all cases, while other measures of fetal growth remained normal. Microcephaly is usually defined in humans as a head circumference that is three standard deviations below average, and other growth defects in the cerebellum and frontal cortex are usually present. The head circumferences of the rhesus fetuses from the study were only between one and three standard deviations below average, and the development of the cerebellum and frontal cortex was normal. Therefore, none of the fetuses had severe enough presentations to be considered microcephalic. Nonetheless, the researchers hypothesize that microcephaly is simply the most severe of a broad range of neurological problems and growth defects that might afflict Zika-infected fetuses, some of which may not even be apparent until childhood development or later on in life.

This study provides evidence of efficient transmission of Zika virus from mother to embryo or fetus during pregnancy, which could also occur in human infections. Consistent with the fact that only 5 percent of human Zika pregnancies in the US territories result in congenital Zika syndrome, the fetuses in this study did not develop any severe birth defects as a result of the infection. However, a previous study from late 2016 described extensive effects on the fetal brain after a pregnant pigtail macaque was infected with a much higher dose of Zika virus. The Wisconsin researchers also discovered that the infection can cause more subtle damage to fetal tissues and may slightly delay brain growth and development, though not to a degree that is included in the definition of microcephaly. The postnatal consequences of these mild abnormalities have yet to be assessed in either humans or non-human primates.

More research will be required to understand the factors that determine whether a fetus develops congenital Zika syndrome or more subtle symptoms like those described in the Wisconsin study. Primates will be an important model for this future work, as well as for testing new treatments that could prevent fetal symptoms during at-risk pregnancies. This work is crucial: the Zika outbreak is still ongoing, and the virus may still spread and establish itself in new areas, putting more pregnancies in danger.

Featured image credit: Oregon National Primate Research Center.

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