Zika Virus Alters Centrosome Architecture to Abrogate Developmental Signaling in the Brain

Key Words: Zika, Innate Immunity, Brain Development, Centrosome

Zika virus (ZIKV) is an arbovirus transmitted by mosquitos and causes neurodevelopmental disorders such as microcephaly in infants. Recent pandemic infections in South and Central America have led to increased cases of microcephaly, a developmental disorder that disrupts brain size, causing cognitive and motor defects. Studies have revealed that ZIKV specifically infects neural stem cells to abrogate neurogenesis in humans and mice. However, the mechanism by which ZIKV disrupts neurogenesis remains unclear.

We have found that ZIKV disrupts centrosome organization, a phenotype associated with inherited forms of microcephaly (MCPH). ZIKV infection causes the formation of aberrant Centrin foci that accumulate the MCPH-associated protein CEP63 and its interacting partner MIB1. The K63-ubiquitin ligase, MIB1 activates the NOTCH signaling and innate immunity pathways that regulate neurodevelopment. As misactivation of either signaling pathway can disrupt neurogenesis, we propose that ZIKV-induced centrosomal disorganization misactivates MIB1 causing aberrant NOTCH signaling and innate immunity preventing timely neuronal differentiation and cortical expansion.

To determine how ZIKV associated centrosome disorganization causes microcephaly, we will investigate how ZIKV disrupts NOTCH signaling, how MIB1 is activated upon ZIKV infection, and how ZIKV activates the innate immunity pathway to alter developmental signaling required for brain development. These studies will provide functional insight into the pathogenesis of ZIKV-associated microcephaly and shed light on the contribution of centrosomes during neurogenesis.