Researchers from the University of California-San Francisco tested the ability of 2,177 FDA-approved compounds to reduce viral proliferation in Zika-susceptible cells.
According to a new study published in the Proceedings of the National Academy of Sciences, researchers from the University of California-San Francisco (UCSF) found that one antibiotic successfully inhibited Zika from infecting fetal brain tissue.
The team of researchers, led by Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and Joseph DeRisi, PhD, chair of the department of Biochemistry and Biophysics at UCSF, co-president of the Chan Zuckerberg Biohub, tried to understand how the Zika virus worked to target the fetal brain and cause microcephaly.
What first sparked the interest of the researchers working in Dr. Kriegstein’s lab, was reading that the Zika virus had the ability to infect AXL protein-containing skin cells. According to a press release, through past research funded by the National Institute of Health, the group had “extensively tracked gene activity and protein production in brain cell types during development,” which lead to their discovery that this particular protein can be found in neural stem cells, among others.
The authors wrote, “In the brain, [Zika] preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia...” These cells contribute to the brain’s development and immunity, among other important roles. The researchers’ findings were especially important in identifying that, contrary to what was discovered in Zika-infected mice, human neurons were not as susceptible to infection with the Zika virus. The researchers found that Zika favored brain cells that expressed AXL, and using lab-grown fetal brain cells, they found that blocking AXL stopped Zika’s infection process.
Following this discovery, the group set out to test compounds that were approved for use in pregnant women by the US Food and Drug Administration. The researchers tested well over 2,100 compounds, and found that azithromycin, a macrolide antibiotic, “reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes.”
The team also noted that the “pattern of viral infection” detected in the lab-grown fetal brain cells was uniform with that of Zika-induced microcephaly observed in infants’ brains. According to Dr. Kriegstein, microcephaly caused by genetic abnormalities is distinctive from that caused by Zika infection; in addition to the brain being underdeveloped, Zika-related microcephaly also causes tissue destruction in the brain, thus shrinking the brain. He stated, “It may be that infections earlier in pregnancy disproportionately affect neural stem cells and later on strongly affect more mature cells, including the growing astrocyte cell population.”
The authors concluded, “Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.” Dr. DeRisi is currently working to launch a clinical trial that would determine if azithromycin can reduce the risks associated with Zika infection in developing fetuses.
Dr. DeRisi commented on the findings, “The development of a vaccine to prevent Zika virus infection and mosquito abatement are important for long-term disease control, but we also want to investigate how the virus infects human tissues and identify treatments that can be used as soon as possible to counter this emerging global disease threat.”
This discovery would potentially change the lives of many women of childbearing age in the Americas as well as in other Zika-endemic regions, since infection with the Zika virus is known to cause several neurologic complications, such as microcephaly. In addition to previously identified neurologic implications of Zika, a recently published study found one infant who was infected with the Zika virus during gestation later developed glaucoma; however, further studies are needed before an official link is made between the viral infection and the eye disease.