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However, despite the importance of neuropathological outcomes, for humans in particular, the pathogenesis, including mode of neuro\u2010invasion, remains unresolved for most congenital virus infections. Using a natural model of congenital infection with an RNA virus, bovine viral diarrhoea virus in pregnant cattle, we sought to delineate the timing and mode of virus neuro\u2010invasion of and spread within the brain of foetuses following experimental respiratory tract infection of the dams at day 75 of pregnancy, a time of maximal risk of tissue pathology without foetal death. Virus antigen was first detected in the foetal brains 14\u2003days postinfection of dams and was initially restricted to amoeboid microglial cells in the periventricular germinal layer. The appearance of these cells was preceded by or concurrent with vasculopathy in the same region. While the affected microvessels were negative for virus antigen, they expressed high levels of the type I interferon\u2010stimulated protein ISG15 and eventually disappeared in parallel with the appearance of microcavitary lesions. Subsequently, the virus spread to neurons and other glial cells. Our findings suggest that the virus enters the CNS via infected microglial precursors, the amoeboid microglial cells, in a \u2018Trojan horse\u2019 mode of invasion and that the microcavitary lesions are associated with loss of periventricular microvasculature, perhaps as a consequence of high, unrestricted induction of interferon\u2010regulated proteins.<\/jats:p>","DOI":"10.1111\/j.1365-2613.2011.00795.x","type":"journal-article","created":{"date-parts":[[2012,1,20]],"date-time":"2012-01-20T15:59:53Z","timestamp":1327075193000},"page":"24-33","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Neuro\u2010invasion by a \u2018Trojan Horse\u2019 strategy and vasculopathy during intrauterine flavivirus infection"],"prefix":"10.1111","volume":"93","author":[{"given":"Helle","family":"Bielefeldt\u2010Ohmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia P.","family":"Smirnova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Airn\u2010Elizabeth","family":"Tolnay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett T.","family":"Webb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo Q.","family":"Antoniazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"van Campen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,1,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-6-49"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00350.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/BF03547277","article-title":"An oculo\u2010cerebellar syndrome caused by congenital bovine viral diarrhoea virus\u2010infection","volume":"25","author":"Bielefeldt\u2010Ohmann H.","year":"1984","journal-title":"Acta Vet. 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