Abstract
Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flaviviridae family, together with dengue, yellow fever, and West Nile viruses. In the wake of its emergence in the French Polynesia and in the Americas, ZIKV has been shown to cause congenital microcephaly. It is the first arbovirus which has been proven to be teratogenic and sexually transmissible. Confronted with this major public health challenge, the scientific and medical communities teamed up to precisely characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. This review focuses on the critical impact of the unfolded protein response (UPR) on ZIKV-associated congenital microcephaly. ZIKV infection of cortical neuron progenitors leads to high endoplasmic reticulum (ER) stress. This results in both the stalling of indirect neurogenesis, and UPR-dependent neuronal apoptotic death, and leads to cortical microcephaly. In line with these results, the administration of molecules inhibiting UPR prevents ZIKV-induced cortical microcephaly. The discovery of the link between ZIKV infection and UPR activation has a broader relevance, since this pathway plays a crucial role in many distinct cellular processes and its induction by ZIKV may account for several reported ZIKV-associated defects.
Highlights
Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flaviviridae family, together with dengue, yellow fever, and West Nile viruses
This review focuses on the critical impact of the unfolded protein response (UPR) on ZIKVassociated congenital microcephaly
These findings supported that ZIKV impairs cell cycle progression, and triggers a cascade of apoptotic and autophagic cell deaths that lead to microcephaly
Summary
Zika virus (ZIKV) was first isolated in 1947 from the Zika forest in Uganda, East Africa (Dick et al, 1952), and identified as a member of the Flaviviridae genus (as yellow fever, West Nile, Japanese encephalitis, and dengue viruses) It remained until recently largely unknown, with fewer than 20 confirmed human infections reported over the 60 years prior to 2007 (Musso and Gubler, 2016). In Brazil, soon after the emergence of ZIKV, microcephalic newborns from ZIKV-infected mothers were reported (Coelho and Crovella, 2017; Saiz et al, 2017), as well as children with postnatal neural and non-neural disorders following congenital ZIKV infection (McCarthy, 2016; Moore et al, 2017; Mavigner et al, 2018) This led to the identification of ZIKV as a teratogenic agent (Baud et al, 2017; Schaub et al, 2017b). The concurrence of this epidemic with the 2016 Summer Olympic Games in Rio de Janeiro further crystallized the global scrutiny on this virus
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