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      Microencephaly in fetal piglets following in utero inoculation of Zika virus

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          Abstract

          Zika virus (ZIKV) is a mosquito-borne flavivirus that became associated with microcephaly in newborns and Guillain–Barré syndrome in adults after its emergence in the Pacific and the Americas in 2015. Newly developed rodent and nonhuman primate models have already revealed important insights into ZIKV-induced neuropathology. Nonhuman primates are phylogenetically closely related to humans and are therefore preferred human surrogates in ZIKV research. However, the use of nonhuman primates, particularly during gestation, raises ethical issues. Considering that pigs also share many anatomical and physiological features with humans, this species may be an attractive alternative human surrogate for ZIKV research. Here, we inoculated 20 porcine fetuses in utero and assessed the effect of ZIKV on brain development 4 weeks later. All inoculated fetuses presented mild to severe neuropathology, characterized by a depletion of neurons in the cerebral cortex. In most cases, neuronal depletion was confined to specific cerebral lobes without affecting brain size, whereas in severe cases a more generalized depletion resulted in microencephaly. Although the virus was widespread in the sows’ placenta at the time of necropsy only low levels of viral RNA were detected in fetal brain samples, thereby preventing the identification of primary target cells. Our findings suggest that pigs can be used to study ZIKV-induced neurodevelopmental defects as currently observed in human neonates, varying from stunted brain growth to localized cortical neuronal depletion in the absence of major macroscopic abnormalities.

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          Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys.

          Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans.
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            Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection.

            Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.
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              The use of pigs in neuroscience: modeling brain disorders.

              The use of pigs in neuroscience research has increased in the past decade, which has seen broader recognition of the potential of pigs as an animal for experimental modeling of human brain disorders. The volume of available background data concerning pig brain anatomy and neurochemistry has increased considerably in recent years. The pig brain, which is gyrencephalic, resembles the human brain more in anatomy, growth and development than do the brains of commonly used small laboratory animals. The size of the pig brain permits the identification of cortical and subcortical structures by imaging techniques. Furthermore, the pig is an increasingly popular laboratory animal for transgenic manipulations of neural genes. The present paper focuses on evaluating the potential for modeling symptoms, phenomena or constructs of human brain diseases in pigs, the neuropsychiatric disorders in particular. Important practical and ethical aspects of the use of pigs as an experimental animal as pertaining to relevant in vivo experimental brain techniques are reviewed. Finally, current knowledge of aspects of behavioral processes including learning and memory are reviewed so as to complete the summary of the status of pigs as a species suitable for experimental models of diverse human brain disorders.
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                Author and article information

                Contributors
                paul.wichgersschreur@wur.nl
                Journal
                Emerg Microbes Infect
                Emerg Microbes Infect
                Emerging Microbes & Infections
                Nature Publishing Group UK (London )
                2222-1751
                29 March 2018
                29 March 2018
                2018
                : 7
                : 42
                Affiliations
                Wageningen Bioveterinary Research, Houtribweg 39, 8221 RA Lelystad, The Netherlands
                Article
                44
                10.1038/s41426-018-0044-y
                5874248
                de06b66e-e468-4041-81e2-4c1c28951c60
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 November 2017
                : 22 January 2018
                : 23 January 2018
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