1 Network of interactions between ZIKA virus 2 non-structural proteins and human host proteins 3

The Zika virus (ZIKV) is a mosquito-borne Flavivirus and can be transmitted through an 21 infected mosquito bite or through human-to-human interaction by sexual activity, blood 22 transfusion, breastfeeding or perinatal exposure. After the 2015-2016 outbreak in Brazil, a strong 23 link between ZIKV infection and microcephaly emerged. ZIKV specifically targets human neural 24 progenitor cells, suggesting that proteins encoded by ZIKV bind and inactivate host cell proteins 25 leading to microcephaly. Here, we present a systematic annotation of interactions between human 26 proteins and the seven non-structural ZIKV proteins corresponding to a Brazilian isolate. The 27 interaction network was generated by combining tandem-affinity purification followed by mass 28 spectrometry with yeast two-hybrid screens. We identified 150 human proteins, involved in 29 distinct biological processes, as interactors to ZIKV non-structural proteins. Our interacting 30 network is composed of proteins that have been previously associated with microcephaly in 31 human genetic disorders and/or animal models. This study builds on previously published 32 interacting networks of ZIKV and genes related to autosomal recessive primary microcephaly to 33 generate a catalog of human cellular targets of ZIKV proteins implicated in processes related to 34 microcephaly in humans. Collectively, this data can be used as a resource for future 35 characterization of ZIKV infection biology and help create a basis for the discovery of drugs which 36 may disrupt the interaction and reduce the health damage to the fetus. 37