Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage

Abstract

Zika virus (ZIKV) infection of pregnant women can result in fetal brain abnormalities. It has been established that ZIKV disrupts neural progenitor cells (NPCs) and leads to embryonic microcephaly. However, the fate of other cell types in the developing brain and their contributions to ZIKV-associated brain abnormalities remain largely unknown. Using intracerebral inoculation of embryonic mouse brains, we found that ZIKV infection leads to postnatal growth restriction including microcephaly. In addition to cell cycle arrest and apoptosis of NPCs, ZIKV infection causes massive neuronal death and axonal rarefaction, which phenocopy fetal brain abnormalities in humans. Importantly, ZIKV infection leads to abnormal vascular density and diameter in the developing brain, resulting in a leaky blood-brain barrier (BBB). Massive neuronal death and BBB leakage indicate brain damage, which is further supported by extensive microglial activation and astrogliosis in virally infected brains. Global gene analyses reveal dysregulation of genes associated with immune responses in virusinfected brains. Thus, our data suggest that ZIKV triggers a strong immune response and disrupts neurovascular development, resulting in postnatal microcephaly with extensive brain damage.

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

“…En este momento, no es posible explicar con claridad las anormalidades neurológicas y el síndrome de Guillain-Barré como efecto directo del virus; además, en el caso del síndrome, no es posible descartar una reacción cruzada entre algunos flavivirus, como el virus del dengue, y la ausencia de anticuerpos antiglucolípidos en pacientes en quienes dicho síndrome se manifestó tempranamente (4,49,50). Las diferencias observadas en los efectos de la infección por el ZIKV en el adulto y en el individuo en desarrollo sugieren que pueden existir diferentes factores que determinan el neurotropismo y la neurotoxicidad.…”

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

“…They also found that ZIKV induced the death of immature and mature neurons and reduced NPC proliferation and differentiation, which resulted in a thinner cortical layer. In both studies, there was no evidence of disruption of cortical lamination and the global transcriptome analyses of infected brains showed the upregulation of genes involved in immune-response-related and apoptosis pathways Shao et al, 2016). Wu et al (2016), however, found the virus mainly in the ventricular zone and striatum of postnatal day 1 mice that were infected at embryonic day 13.5.…”

Zika Virus Disease: The Situation in Turkey and a Review of the Worldwide Outbreak

“…ZV kortikal gelişimin farklı evrelerinde etki ederek anormal hücre proliferasyonu/apoptoz, anormal nöronal migrasyon ya da anormal postmigrasyona neden olur (31). Diğer olası mikrosefali nedenleri, genetik anomaliler, gebelikte geçirilen bazı infeksiyonlar (STORCH: sifilis, toksoplazmoz, rubella, sitomegalovirus, herpes simpleks virusu, HIV ve diğer viruslar), annenin gebelikte toksinlere ve kimyasallara maruz kalması, fetal alkol sendromu, radyasyon, diabetes mellitus gibi metabolik hastalıklar, malnütrisyon, postpartum serebrovasküler ve nonvasküler (menenjit, ensefalit, bakır zehirlenmesi, kronik böbrek yetmezliği) hasarlardır (30,31).…”

“…Diğer olası mikrosefali nedenleri, genetik anomaliler, gebelikte geçirilen bazı infeksiyonlar (STORCH: sifilis, toksoplazmoz, rubella, sitomegalovirus, herpes simpleks virusu, HIV ve diğer viruslar), annenin gebelikte toksinlere ve kimyasallara maruz kalması, fetal alkol sendromu, radyasyon, diabetes mellitus gibi metabolik hastalıklar, malnütrisyon, postpartum serebrovasküler ve nonvasküler (menenjit, ensefalit, bakır zehirlenmesi, kronik böbrek yetmezliği) hasarlardır (30,31). Brezilya'da 2016 itibariyle ZV'ye bağlı 3530 mikrosefali ve 46 ölüm bildirilmiş-tir (32).…”