Predicted protein interactions of IFITMs may shed light on mechanisms of Zika virus-induced microcephaly and host invasion.

After the first reported case of Zika virus (ZIKV) in Brazil, in 2015, a significant increase in the reported cases of microcephaly was observed. Microcephaly is a neurological condition in which the infant's head is significantly smaller with complications in brain development. Recently, two small membrane-associated interferon-inducible transmembrane proteins (IFITM1 and IFITM3) have been shown to repress members of the flaviviridae family which includes ZIKV. However, the exact mechanisms leading to the inhibition of the virus are yet unknown. Here, we assembled an interactome of IFITM1 and IFITM3 with known protein-protein interactions (PPIs) collected from publicly available databases and novel PPIs predicted using the High-confidence Protein-Protein Interaction Prediction (HiPPIP) model. We analyzed the functional and pathway associations of the interacting proteins, and found that there are several immunity pathways (toll-like receptor signaling, cd28 signaling in T-helper cells, crosstalk between dendritic cells and natural killer cells), neuronal pathways (axonal guidance signaling, neural tube closure and actin cytoskeleton signaling) and developmental pathways (neural tube closure, embryonic skeletal system development) that are associated with these interactors. Our novel PPIs associate cilia dysfunction in ependymal cells to microcephaly, and may also shed light on potential targets of ZIKV for host invasion by immunosuppression and cytoskeletal rearrangements. These results could help direct future research in elucidating the mechanisms underlying host defense to ZIKV and other flaviviruses.