부산대학교 도서관

Zika virus (ZIKV) infection in pregnancy can produce catastrophic teratogenic damage to the developing fetus including microcephaly and congenital Zika syndrome (CZS). We previously described fetal CNS pathology occurring by three weeks post-ZIKV inoculation in Olive baboons at mid-gestation, including neuroinflammation, loss of radial glia (RG), RG fibers, neuroprogenitor cells (NPCs) resulting in disrupted NPC migration. In the present study, we explored fetal brain pathologies at term gestation resulting from ZIKV exposure during either first or second trimester in the Olive baboon. In all dams, vRNA in whole blood resolved after 7 days post inoculation (dpi). One first trimester infected dam aborted at 5 dpi. All dams developed IgM and IgG response to ZIKV with ZIKV IgG detected in fetal serum. Placental pathology and inflammation were observed including disruption of syncytiotrophoblast layers, delayed villous maturation, partially or fully thrombosed vessels, calcium mineralization and fibrin deposits. In the uterus, ZIKV was detected in ¾ first trimester but not in second trimester infected dams. While ZIKV was not detected in any fetal tissue at term, all fetuses exhibited varying degrees of neuropathology. Fetal brains from ZIKV inoculated dams exhibited a range of gross brain pathologies including irregularities of the major gyri and sulci of the cerebral cortex and cerebellar pathology. Frontal cortices of ZIKV fetuses showed a general disorganization of the six-layered cortex with degree of disorganization varying among the fetuses from the two groups. Frontal cortices from ZIKV inoculation in the first but not second trimester exhibited increased microglia, and in both trimester ZIKV inoculation, increased astrocyte numbers (white matter). In the cerebellum, increased microglia were observed in fetuses from both first and second trimester inoculation. In first trimester ZIKV inoculation, decreased oligodendrocyte precursor cell populations were observed in fetal cerebellar white matter. In general, our observations are in accordance with those described in human ZIKV infected fetuses. Author summary: Infection of pregnant women with Zika virus can cause severe birth defects and disabilities in the developing fetus with microcephaly as the characteristic zika specific neuropathology. Being natural hosts for this virus, non-human primates (NHPs) have provided excellent models to understand the origins of fetal brain damage induced by Zika virus. In a previous study using the baboon as a non-human primate model for Zika virus infection, we observed neuronal precursor and glial cells targeting by Zika virus in the fetal brain during the early stages after inoculation of the pregnant baboons. In this study, we infected pregnant baboons in either the first or second trimesters with Zika virus and examined fetal brains at the end of pregnancy. Fetuses from the infected dams exhibited a range of visible brain pathology such as defects in brain folding and cerebellar damage. In the frontal cortex, fetuses showed a general neuronal disorganization in the cortex in both first and second trimester infected pregnancies, with a wide variation in the severity of defects noted. Fetuses from first trimester infected baboon mothers showed greater damage compared to the second trimester infected baboons. In general, our observations are in accordance with those described in humans infected with Zika virus. [ABSTRACT FROM AUTHOR]