Fok-Moon Lum1, Donovan K S Low1, Yiping Fan2, Jeslin J L Tan1, Bernett Lee1, Jerry K Y Chan1,2,3,4, Laurent Rénia1, Florent Ginhoux1, Lisa F P Ng1,5. 1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR). 2. Department of Reproductive Medicine and. 3. KK Research Centre, KK Women's and Children's Hospital, and. 4. Cancer and Stem Cell Program, Duke-NUS Medical School, Singapore; and. 5. Institute of Infection and Global Health, University of Liverpool, United Kingdom.
Abstract
BACKGROUND: The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. METHODS: Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays. RESULTS: We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1). CONCLUSIONS: Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.
BACKGROUND: The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. METHODS: Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays. RESULTS: We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1). CONCLUSIONS: Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.
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