Human Fetal Astrocytes Infected with Zika Virus Exhibit Delayed Apoptosis and Resistance to Interferon: Implications for Persistence.

Daniel Limonta,Leina Saito,Shangmei Hou,Juan Jovel,Andrew Mason,Tom Hobman,Anil Kumar,Gane Ka-Shu Wong,Christopher Power,William Branton,Adriana Airo

doi:10.3390/v10110646

Daniel Limonta, Leina Saito + Show 9 more

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https://doi.org/10.3390/v10110646

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Abstract

Zika virus (ZIKV) infection and persistence during pregnancy can lead to microcephaly and other fetal neurological disorders collectively known as Congenital Zika Syndrome. The immunological and virological events that contribute to the establishment of persistent ZIKV infection in humans are unclear though. Here we show that human fetal astrocytes (HFAs), the most abundant cell type in the central nervous system, become persistently infected with ZIKV resulting in continuous viral shedding for at least one month; a process that is facilitated by TIM/TAM receptors. HFAs are relatively resistant to ZIKV-induced apoptosis, a factor that may be important for chronic infection of these cells. Once infection was established, interferon treatment did not reduce virus replication. Moreover, the fact that the innate immune system was highly activated in persistently infected HFAs indicates that the virus can thrive in the presence of a sustained antiviral response. RNAseq analyses of persistently infected cells revealed that ZIKV alters host gene expression in a manner that could affect developmental processes. Conversely, data from sequencing of ZIKV genomes in persistently infected HFAs suggest that adaptive mutations were not required for establishing chronic infection. Based on these results, we postulate that HFAs are reservoirs for ZIKV in the fetal brain and that moderate apoptosis combined with inefficient antiviral response from these cells may contribute to the establishment of chronic brain infection associated with the ZIKV neurodevelopmental abnormalities.

Highlights

Zika virus (ZIKV) is an arthropod-borne virus of the genus Flavivirus, family Flaviviridae
human fetal astrocytes (HFAs) were infected with ZIKV (MOI = 3) and replication was assessed by measuring viral genomic RNA 1–5 days post-infection
Representative primary data from the flow cytometry analyses of A549 cells and HFAs are included in the supplementary material (Figure S6). These results indicate that while a pool of HFAs is highly permissive to infection by ZIKV, the cells are comparatively resistant to virus-induced apoptosis

Summary

Introduction

Zika virus (ZIKV) is an arthropod-borne virus of the genus Flavivirus, family Flaviviridae. It was first isolated approximately 70 years ago in the Zika forest of Uganda [1]. Viruses 2018, 10, 646 and South Asia but other than an undifferentiated febrile syndrome with rash and arthralgia, ZIKV infections were of little consequence. Prolonged ZIKV infection of fetal cells and tissues that serve as reservoirs for the virus are needed to establish persistence during pregnancy. A number of animal and in vitro models describing the tropism and pathogenesis of the ZIKV infection have recently been published [4,5,6] but the immune and viral mechanisms involved in chronic infection of human fetal brain cells are not completely understood

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