Advances in congenital Zika syndrome and its pathogenesis

Abstract

<p indent=0mm>Zika virus (ZIKV), originally discovered in a sentinel rhesus monkey in Zika valley in Uganda in 1947, has long been viewed as a classical mosquito-borne flavivirus. Due to its association with only a mild and self-limiting illness, ZIKV was a neglected pathogen following <sc>60 years</sc> since its identification. However, this virus became a serious public health concern in 2015−2016 outbreak in the Americas because of its association with congenital Zika syndrome (CZS). World Health Organization (WHO) declared the ZIKV outbreak a public health emergency of international concern in 2016. CZS is a pattern of birth defects found among fetuses and babies infected with ZIKV during pregnancy. The main clinical features of CZS are variable including severe microcephaly, decreased brain tissue, meningitis, damage to the back of the eye, hearing defects, arthrogryposis as well as hypertonia restricting body movement soon after birth. Benefiting from close collaboration of the international scientific community, intensive studies have been performed in development of experimental models to gain insights into the molecular basis of CZS in humans. These models include cultured neuroprogenitor stem cells, cortical organoids, especially mouse and nonhuman primate animal models which recapitulate many features of CZS in humans. Thanks to these models, questions related to how ZIKV infection causes congenital disease have been largely answered. For example, ZIKV was found to directly infects human neural progenitor cells (hNPCs) of the cerebral cortex, resulting in reduced hNPC proliferation; ZIKV also exhibits tropism for microglia in the brain, leading to production of inflammatory cytokines that inhibit neuronal precursor cell proliferation and differentiation. Additionally, studies have suggested that ZIKV can infect and trigger inflammasome pathways and innate antiviral immune responses of glial cells. While remarkable progress has been made to explain the associated underlying mechanisms, many unanswered key questions remain as follows: (1) How is the placenta in different developmental stage susceptible to ZIKV infection? (2) How is ZIKV transmitted across the placenta to infect the fetus? (3) What is the neurodevelopmental sequelae of congenital infection? (4) How does pre-existing maternal flavivirus immunity impact pregnancy-associated disease? Overall, due to collaborative and multidisciplinary efforts, a large body of knowledge of ZIKV biology has been obtained that has deepened our understanding of the CZS and informed the development of candidate vaccines and therapies. The lessons we have learned from ZIKV could enable effective preparation for the ultimate control of emergence of new congenital viral diseases in the future.