How does Zika virus cause microcephaly?

Abstract

The re-emergence of Zika virus (ZIKV), a mosquito-borne and sexually transmitted flavivirus circulating in >70 countries and territories, poses a significant global threat to public health due to its ability to cause severe developmental defects in the human brain, such as microcephaly. Since the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern, remarkable progress has been made to gain insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection. Here we review the current knowledge and progress in understanding the impact of ZIKV exposure on the mammalian brain development and discuss potential underlying mechanisms.

Keywords: Zika virus; brain development; microcephaly.

Figure 1.

ZIKV genome structure and signaling transductions underlying ZIKV infection. (A) A diagram of ZIKV genomic RNA. (Red arrows) Mutations in the Brazilian strain of ZIKV compared with the French Polynesian strain; (blue arrows) mutations in the Asian strain compared with the African strain; (purple arrow) a mutation of the Brazilian strain in the E protein Asn154. (B) A diagram showing the viral replication pathway and pathogenesis pathways activated upon ZIKV infection.

Figure 2.

Vertical transmission of ZIKV and its impact on human fetal development. ZIKV could be transmitted to a pregnant woman via the bite of an infected Aedes mosquito, which could be further vertically transmitted from the infected mother to the fetus by infecting placental trophoblasts and macrophages (Hofbauer cells) and crossing the placental barrier.

Figure 3.

Investigation of neurotropism of ZIKV infection in vitro and in vivo. The effects of ZIKV on brain development and the underlying mechanisms could be explored with in vitro models, such as NPCs, astrocytes, and three-dimensional (3D) brain organoids derived from either hiPSCs or primary human brain tissue, or in vivo animal models, such as mouse models at multiple developmental stages (i.e., prenatal and postnatal stages) by infection of ZIKV through subcutaneous inoculation, intravenous injection, or intraperitoneal injection in pregnant immune-competent mice or direct injection of ZIKV into developing fetal mouse brains.

Figure 4.

Mechanisms underlying impaired brain development upon ZIKV infection. ZIKV directly targets NPCs in the developing brain and activates innate immune response, which could lead to dysregulation of genes involved in cell cycle, neurogenesis, and apoptosis, resulting in increased cell death, disrupted cell cycle progression, reduced proliferation, and premature differentiation. On the other hand, infection of ZIKV in placenta and glial cells, including astrocytes and microglia, could lead to placental insufficiency and activation of immune response (inflammation), which may elicit non-cell-autonomous effects on NPCs, neurons, and vasculature, resulting in impaired neurogenesis and microcephaly.