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The rapid spread of Zika virus (ZIKV) and its association with 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 virus-induced 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.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here, we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties of Pcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type with Pcdhg-deficient interneuron precursors further reduced mutant cIN survival, but the proportion of mutant and wild-type cells undergoing cell death was not affected by their density. Transplantation also allowed us to test for the contribution of Pcdhg isoforms to the regulation of cIN cell death. We conclude that Pcdhg, specifically Pcdhgc3, Pcdhgc4, and Pcdhgc5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain. After completing their migration into cortex, their final numbers are adjusted -during a period of postnatal development - by programmed cell death. The mechanisms that regulate cIN elimination remains controversial. Here we show that genes in the protocadherin (Pcdh)-γ gene cluster, but not in the Pcdh-α or Pcdh-β clusters, are required for the survival of cINs through a BAX-dependent mechanism. Surprisingly, the physiological and morphological properties of Pcdh-γ deficient and wild type cINs during cIN cell death were indistinguishable. Co-transplantation of wild type and Pcdh-γ deficient interneuron precursor cells demonstrate that: 1) the number of mutant cINs eliminated was much higher than that of wild type cells, but the proportion of mutant or WT cells undergoing cell death was not affected by their density; 2) the presence of mutant cINs increases cell death among wild-type counterparts, and 3) cIN survival is dependent on the expression of Pcdh-γ C3, C4, and C5. We conclude that Pcdh-γ , and specifically γC3, γC4, and γC5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death. Footnotes * Information about authors, acknowledgements, and general text was updated.

The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including placental damage and microcephaly. However, the placenta's role in viral transmission and the mechanisms of microcephaly have not been addressed in primary human tissues. Moreover, there is an urgent need for drugs that can prevent developmental defects following infection. Here, we identify the placental and brain cell populations most susceptible to ZIKV infection, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by inhibiting viral proliferation. In the early gestation placenta, the virus readily infected trophoblast subpopulations that are in direct contact with maternal blood and uterine cells, suggesting routes of ZIKV transmission to the embryo and fetus. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, 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 and brain abnormalities caused by third trimester infection. Blocking a putative viral entry receptor, AXL, which is highly enriched in the infected placenta and brain cell types, reduced ZIKV infection of astrocytes in vitro. In a glial cell line, the macrolide antibiotic, azithromycin, inhibited viral proliferation and viral-induced cytopathic effects at clinically relevant concentrations. Our characterization of infection in primary human tissues clarifies the pathogenesis of congenital ZIKV infection and provides critical context for interpreting results from model systems. Further work on azithromycin and related compounds may yield additional therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.