The Brazilian Zika virus strain causes birth defects in experimental models

Abstract

Summary Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (Family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys1. Until the 20th century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the island of Yap in Micronesia2. Patients experienced fever, skin rash, arthralgia and conjunctivitis2. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America3. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome4,5. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKVBR) strain causes birth defects remains missing6. Here we demonstrate that the ZIKVBR infects fetuses, causing intra-uterine growth restriction (IUGR), including signs of microcephaly in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. Finally, we observed that the infection of human brain organoids resulted in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKVBR crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKVBR outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKVBR in human neurodevelopment.

Zika virus disease: a current review of the literature

“…Recently, a few studies [79,80,[82][83][84][85] have evidenced the pathogenic potential of Brazilian strain of ZIKV during the development of fetus in animal models. These studies concluded that ZIKV first infects the placenta and then the brain of fetus, where it preferentially infects neural progenitor cells and decreases their viability and growth as neurospheres through down-regulation of genes that are involved in cell and organ development, and up-regulation of genes that are involved in immune responses.…”

“…This results in inhibited cellular proliferation and differentiation, neuronal apoptosis, thinning of the cortex and macroscopic features similar to microcephaly. Based on the results of the above stated studies [79,80,[82][83][84][85], a causal link between ZIKV infection and microcephaly could be hypothesized.…”

Translational potential of human brain organoids

“…Several research groups applied the brain organoid model to study Zika infection, a current epidemic that has been strongly linked to newborn microcephaly 35, 46, 47, 48, 49, 50. These studies have provided evidence that human neural stem cells are selectively vulnerable35, 48 and more susceptible to premature differentiation50 upon Zika virus infection, providing a molecular explanation for the observed microcephaly.…”

Modeling Williams syndrome with induced pluripotent stem cells

“…Thus, 2D neuronal cultures could possibly recapitulate only cellular defects occurring during early stages of brain development and the findings obtained from such models must be cautiously interpreted. Recently, the development of 3D culture system resulting in brain organoids has been reported, [36][37][38] offering more closely relevant in vitro models for mature brain organization and cellular network. Different differentiation protocols have been developed and fine-tuned to generate organoids with different particular brain region identity, 37,39 potentially allowing study of pathological effects focusing on specific yet complex 3D brain-like structures.…”