Zika Research Gathers Pace

After weighing up the latest evidence, scientists from the Centers for Disease Control and Prevention (CDC) have declared that there is a “causal relationship” between Zika infection during pregnancy and birth defects. The researchers detail their conclusions in a special report in the New England Journal of Medicine (1).

In a related press release, the CDC retained a note of caution, “The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria supports the authors’ conclusions” (2).

Wanting to add weight to the overall body of evidence, a team of Brazilian scientists recently published work examining the effects of the virus on human neural stem cells grown as neurospheres and brain organoids (3). Neurospheres are simple clusters of free-floating neural stem cells that recapitulate the early characteristics of neurogenesis, while brain organoids are more complex bundles of neural tissue, possessing many features of the first trimester fetal brain. The researchers’ observed Zika virus particles on the cell surface and in mitochondria and vesicles of the neural cells. All of the Zika-infected neurospheres suffered cell death to some degree, suggesting that the virus could impair early brain formation. Cell death was also observed in brain organoids infected with Zika, stunting their growth by 40 percent, compared with mock-infected cells. In comparison, brain organoids infected with dengue virus, which is not associated with birth defects, showed few ill effects.

In vitro tissue models like brain organoids are proving very useful in Zika research; they are cheaper, faster and less complex than working with rat or mouse models. Another study investigating Zika’s effects on neurospheres and brain organoids has shed light on how the virus causes cell death (4). The researchers, based at University of California, San Diego, discovered that Zika infections lead to upregulation of toll-like receptor 3 (TLR3), an immune receptor that triggers the cells’ self-destruct mechanisms. The researchers identified a number of TLR3-related genes responsible for the upregulation (NTN1, EPHA3, ADGRB3, EPHB2, SLITRK5, and GRIK2), but further investigation is needed to determine their precise role. Importantly, they found that the stunted growth of Zika-infected neurospheres and brain organoids could be tempered by adding TLR3 inhibitors into the culture, which indicates that specialized TLR3 inhibitors could reduce the impact of Zika on fetal brain development.