Zika virus cell tropism in the developing human brain and inhibition by azithromycinHanna Retallack, Elizabeth Di Lullo, Carolina Arias Kristeene A. Knopp, Matthew T. Laurie, Carmen Sandoval-Espinosa, Walter R. Mancia Leon, Robert Krencik, Erik M. Ullian, Julien Spatazza, Alex A. Pollen, Caleigh Mandel-Brehm, Tomasz J. Nowakowski, Arnold R. Kriegstein, and Joseph L. DeRisi
PNAS, 2017Abstract: The rapid spread of Zika virus (ZIKV) and its associationwith abnormal
brain development constitute a global health emergency. Congenital
ZIKV infection produces a range of mild to severe pathologies,
including microcephaly. To understand the pathophysiology of ZIKV
infection, we used models of the developing brain that faithfully
recapitulate the tissue architecture in early to midgestation. We
identify the brain cell populations that are most susceptible to ZIKV
infection in primary human tissue, provide evidence for a mechanism
of viral entry, and show that a commonly used antibiotic protects
cultured brain cells by reducing viral proliferation. In the brain, ZIKV
preferentially infected neural stem cells, astrocytes, oligodendrocyte
precursor cells, and microglia, whereas neurons were less susceptible
to infection. These findings suggest mechanisms for microcephaly and
other pathologic features of infants with congenital ZIKV infection
that are not explained by neural stem cell infection alone, such as
calcifications in the cortical plate. Furthermore, we find that blocking
the glia-enriched putative viral entry receptor AXL reduced ZIKV
infection of astrocytes in vitro, and genetic knockdown of AXL in a
glial cell line nearly abolished infection. Finally, we evaluate 2,177
compounds, focusing on drugs safe in pregnancy. We show that the
macrolide antibiotic azithromycin reduced viral proliferation and virusinduced
cytopathic effects in glial cell lines and human astrocytes. 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.
