+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: not found

      Zika virus cell tropism in the developing human brain and inhibition by azithromycin


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly spread through the Americas and has been associated with fetal abnormalities, including microcephaly. To understand how microcephaly develops, it is important to identify which cell types of the developing brain are susceptible to infection. We use primary human tissue to show that radial glia and astrocytes are more susceptible to infection than neurons, a pattern that correlates with expression of a putative viral entry receptor, AXL. We also perform a screen of Food and Drug Administration-approved compounds, with an emphasis on drugs known to be safe in pregnancy. We identify an antibiotic, azithromycin, that reduces viral proliferation in glial cells, and compare its activity with daptomycin and sofosbuvir, two additional drugs with anti-ZIKV activity.


          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.

          Related collections

          Most cited references15

          • Record: found
          • Abstract: found
          • Article: not found

          Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

          In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
            • Record: found
            • Abstract: found
            • Article: not found

            Primary microcephaly: do all roads lead to Rome?

            The relatively large brain and expanded cerebral cortex of humans is unusual in the animal kingdom and is thought to have promoted our adaptability and success as a species. One approach for investigating neurogenesis is the study of autosomal recessive primary microcephaly (MCPH), in which prenatal brain growth is significantly reduced without an effect on brain structure. To date, eight MCPH loci and five genes have been identified. Unexpectedly, all MCPH proteins are ubiquitous and localise to centrosomes for at least part of the cell cycle. Here, we focus on recent functional studies of MCPH proteins that reveal the centrosome as a final integration point for many regulatory pathways affecting prenatal neurogenesis in mammals.
              • Record: found
              • Abstract: found
              • Article: not found

              Specification of transplantable astroglial subtypes from human pluripotent stem cells.

              Human pluripotent stem cells (hPSCs) have been differentiated efficiently to neuronal cell types. However, directed differentiation of hPSCs to astrocytes and astroglial subtypes remains elusive. In this study, hPSCs were directed to nearly uniform populations of immature astrocytes (>90% S100β(+) and GFAP(+)) in large quantities. The immature human astrocytes exhibit similar gene expression patterns as primary astrocytes, display functional properties such as glutamate uptake and promotion of synaptogenesis, and become mature astrocytes by forming connections with blood vessels after transplantation into the mouse brain. Furthermore, hPSC-derived neuroepithelia, patterned to rostral-caudal and dorsal-ventral identities with the same morphogens used for neuronal subtype specification, generate immature astrocytes that express distinct homeodomain transcription factors and display phenotypic differences of different astroglial subtypes. These human astroglial progenitors and immature astrocytes will be useful for studying astrocytes in brain development and function, understanding the roles of astrocytes in disease processes and developing novel treatments for neurological disorders.

                Author and article information

                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                13 December 2016
                29 November 2016
                29 November 2016
                : 113
                : 50
                : 14408-14413
                [1] aDepartment of Biochemistry and Biophysics, University of California, San Francisco , CA 94158;
                [2] bEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco , CA 94143;
                [3] cDepartment of Neurology, University of California, San Francisco , CA 94158;
                [4] dDepartment of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara , CA 93106;
                [5] eDepartment of Ophthalmology, University of California, San Francisco , CA 94122;
                [6] fCenter for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute , Houston, TX 77030;
                [7] gDepartment of Neurological Surgery, University of California, San Francisco , CA 94143
                Author notes
                2To whom correspondence may be addressed. Email: kriegsteina@ 123456stemcell.ucsf.edu or joe@ 123456derisilab.ucsf.edu .

                Contributed by Joseph L. DeRisi, November 1, 2016 (sent for review October 7, 2016; reviewed by Nenad Sestan and Pei-Yong Shi)

                Author contributions: H.R., E.D.L., C.A., K.A.K., M.T.L., A.A.P., T.J.N., A.R.K., and J.L.D. designed research; H.R., E.D.L., C.A., K.A.K., M.T.L., C.S.-E., W.R.M.L., J.S., and C.M.-B. performed research; R.K. and E.M.U. contributed new reagents/analytic tools; H.R., E.D.L., C.A., K.A.K., M.T.L., C.S.-E., W.R.M.L., J.S., C.M.-B., and T.J.N. analyzed data; and H.R., E.D.L., C.A., K.A.K., M.T.L., A.A.P., T.J.N., A.R.K., and J.L.D. wrote the paper.

                Reviewers: N.S., Yale University School of Medicine; and P.-Y.S., University of Texas Medical Branch.

                1H.R. and E.D.L. contributed equally to this work.

                PMC5167169 PMC5167169 5167169 201618029

                Freely available online through the PNAS open access option.

                Page count
                Pages: 6
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: R01NS075998
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: U01 MH105989
                Funded by: Howard Hughes Medical Institute (HHMI) 100000011
                Award ID: n/a
                Funded by: HHS | NIH | National Institute of Mental Health (NIMH) 100000025
                Award ID: R01MH099595-01
                Funded by: Paul G. Allen Family Foundation 100000952
                Award ID: n/a
                Funded by: Damon Runyon Cancer Research Foundation (Damon Runyon) 100001021
                Award ID: n/a
                Biological Sciences

                Zika virus,cortical development,azithromycin,microcephaly


                Comment on this article