Abstract
Despite being perceived to be a relatively innocuous pathogen during its circulation in Africa in the 20th century, consequent outbreaks in French Polynesia and Latin America revealed the Zika virus (ZIKV) to be capable of causing severe neurological defects. Foetuses infected with the virus during pregnancy developed a range of pathologies including microcephaly, cerebral calcifications and macular scarring. These are now collectively known as Congenital Zika syndrome (CZS). It has been established that the neuropathogenesis of ZIKV results from infection of neural progenitor cells in the developing cerebral cortex. Following this, two main hypotheses have emerged: the virus causes either apoptosis or premature differentiation of neural progenitor cells, reducing the final number of mature neurons in the cerebral cortex. This review describes the cellular processes which could potentially cause virus induced apoptosis or premature differentiation, leading to speculation that a combination of the two may be responsible for the pathologies associated with ZIKV. The review also discusses which specific lineages of the ZIKV can employ these mechanisms. It has been unclear in the past whether the virus evolved its neurotropic capability following circulation in Africa, or if the virus has always caused microcephaly but public health surveillance in Africa had failed to detect it. Understanding the true neuropathogenesis of ZIKV is key to being prepared for further outbreaks in the future, and it will also provide insight into how neurotropic viruses can cause profound and life-long neurological defects.
Highlights
The Zika virus (ZIKV) was first identified in a febrile monkey in Uganda in 1947, and circulated through the African continent, causing either an asymptomatic or self-resolving influenza like illness
neural progenitor cells (NPCs) infected with Asian ZIKV show increased levels of endoplasmic reticulum (ER) stress markers such as calnexin and calreticulin, and the upregulation of proteins involved in the PERK-eIF2α-ATF4 pathway, a signalling cascade of the unfolded protein response (UPR) (Gladwyn-Ng et al, 2018)
This review discusses that the neuropathogenic effects of foetal ZIKV infection cannot be attributed to a single mechanism, but rather the cumulative effect of multiple pathways that either result in the premature differentiation or apoptosis of NPCs in the developing cerebral cortex
Summary
The Zika virus (ZIKV) was first identified in a febrile monkey in Uganda in 1947, and circulated through the African continent, causing either an asymptomatic or self-resolving influenza like illness. Studies have consistently shown that Asian/American and African ZIKV can infect NPCs in the developing cerebral cortex. Asian ZIKV has been shown to localise to apical NPCs at the ventricular zone, and whilst African ZIKV shares this tropism, it can infect neurons in the primitive cortical region (Figure 4, right) (Qian et al, 2016; Gabriel et al, 2017).
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