The impact of Zika virus in the brain

https://doi.org/10.1016/j.bbrc.2017.01.074Get rights and content

Highlights

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    ZIKV infects cells from the CNS and causes cell death.

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    ZIKV causes brain damage in fetuses in any time of pregnancy.

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    ZIKV can cause neuropathies in adults.

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    ZIKV infects preferentially Neuroprogenitor cells in fetuses and adults.

Abstract

The recent outbreak of ZIKV in Brazil called the attention of the world because the effects of viral infection in the brain under development in fetuses. Consequences of vertical infection comprise brain malformation, especially microcephaly, eye and musculoskeletal abnormalities, among others. In adults, outcomes of infection include meningoencephalitis and Guillain-Barré Syndrome. Recent data specific suggest that neural progenitor cells are the main targets of ZIKV infection, causing massive cellular death and impairment in the neurogenesis process. Here we review the fetal and adult brain damage after ZIKV exposure, exploring models to study the mechanisms underlying the pathways related to microcephaly and cell death.

Introduction

Zika virus (ZIKV) is a mosquito-borne flavivirus that was first isolated from a Rhesus monkey in 1947, in the Zika forest in Uganda, and subsequently found in Aedes africanus mosquitoes [1], [2]. Aedes Aegypti mosquito is the main vector responsible for transmitting ZIKV and, more recently, sexual and maternal to fetal transmission have been related [3], [4], [5], [6]. Since the disease is an arboviruses, ZIKV has emerged in recent years and spread in the Pacific and Americas [3], [7], [8].

Recently, the association between ZIKV infection and congenital malformation has been described in newborns. In 2015, an increase in the number of newborns with microcephaly was reported in Brazil [9], [10], [11]. Although microcephaly has received most of the attention as a consequence of ZIKV infection during the pregnancy, a spectrum of fetal malformations has been described and it is actually referred as congenital Zika syndrome (CZS) [12]. This syndrome includes developmental abnormalities in ocular, craniofacial, musculoskeletal, pulmonary systems among other manifestations [12]. However, the effects of the virus in the central nervous system (CNS) seems devastating, as a consequence of the neurotropism of the ZIKV [13], [14].

Not only the brain under development is a target for ZIKV, but adults who are infected with the virus can also develop neurological damage. Meningoencephalitis was described in an 81-year-old male from an endemic ZIKV region [15]. Although this is a single case, this report highlights a possible outcome for ZIKV infection in the adult brain.

Other neurological clinical manifestations related to ZIKV have been reported. Acute flaccid paralysis (AFP) is a progressive weakness reported in subacute infection, usually requiring respiratory assistance. AFP can be manifested by two independent mechanisms, myelitis with motor neuron damage or Guillain-Barré Syndrome (GBS), a post-infectious and demyelinating polyradiculopathy, mediated by the immune system [16], [17].

Here, we review the effects of ZIKV infection in the brain under development and the consequences of this infection, addressing models that have been used in vitro and in vivo to study the pathogenicity of ZIKV, as well as platforms that have been used to test drugs against the virus.

Section snippets

Brain damage and microcephaly

ZIKV infection was considered mild and was not a topic that brought public healthy relevance [12]. Conversely, starting in May 2015, in Brazil, Brazilian physicians raised the red flag after realizing an increased number of newborns with microcephaly [18]. Besides that, a series of brain malformations were identified during routine ultrasound, such as abnormal arterial flow, severe cerebral atrophy, intracranial calcifications, and ventriculomegaly [11], [18], [19]. However, just in April 2016,

In vitro and in vivo models to study ZIKV infection

Many groups of scientists in the world have been studying the cellular basis for development of microcephaly in fetuses infected with ZIKV. The use of in vitro and in vivo models presented as very important to better understanding the mechanisms of ZIKV and demonstrated a neurotropism by the virus [23], [24]. In vitro systems were successfully developed using the advances in stem cells field, like the development of induced pluripotent stem cells (iPSC) and embryonic stem cell lineages (ESC)

Neuroprogenitors cells are preferential targets for ZIKV

Neuroprogenitor cell (NPC) or Neuro stem cells (NSCs) are the stem cells in the brain, that are able to differentiate in many cell types that form the layers of the brain, depending on the stimuli [26]. Considering a brain under development, and specially the first trimester of the gestation, NPCs are probably the majority of the cells in the CNS [26]. Using this hypothesis, NPCs were the cells to be challenged against ZIKV. Fortunately, human NPCs could be derived from induced Pluripotent Stem

The advances made by using brain organoids

Brain organoids are profitable models to study the mechanism involved in microcephaly. These organoids recapitulate crucial features of brain development. Since they were produced, a lot of researches have been done using this model [44], [45]. The organoid technology has been used to address the link between ZIKV and microcephaly.

After infection with the prime-strain MR766, organoids decreased in the overall size, correlating that with the viral replication [28], [46]. Also, human brain

In vivo models

ZIKV has been linked with the recent outbreak of newborns with microcephaly. However, initially the correlation was made considering just epidemiological findings, focusing on mothers with ZIKV infection and their newborns with microcephaly [18]. Strong evidence of this correlation was made when viral particles were found inside the brain of a fetuses whose mother was ZIKV infected during pregnancy [22]. However, irrefutable evidences were made when a pregnant SJL mouse infected with the

Treatment and prevention

The treatment for ZIKV infection is an urgent requirement, especially avoiding the congenital syndrome. Currently, there are no approved therapies to prevent or to treat ZIKV infection. Researchers have been focusing in FDA approved drugs, but virtual screening could be very useful to identify possible hints. Actually, there is a project called Open Zika that offers virtual screening to detect these hints [59]. To validate these hints, wet labs have been used a platform based on NPCs behavior,

Concluding remarks

Concerning ZIKV infection in the CNS, researches made from independent laboratories around the world have been pointing out NPCs as ZIKV main target. This could explain the pathological findings in brains of newborns infected by vertical transmission, like microcephaly. In addition, for adult neurological outcomes the main target cells are still unknown. Considering that the adult brain also has NPCs, responsible for brain plasticity, maintenance and cognition, our hypothesis is that NPCs from

Conflict of interest

The authors declare no conflict of interest.

Acknowledgment

We would like to thank Anita J. Brito for the writing review. This work was supported by grants from the Zika Network FAPESP projects 2011/18703-2 and 2014/17766-9 and the NGO “The Tooth Fairy Project”.

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