Impact Host ANKLE2 on the replication of ZIKV

Abstract

Zika virus became well known in recent years due to an outbreak in the Americas in 2015-2016. This virus spreads though the bites of infected yellow fever mosquitos (Aedes aegypti) that are found in the warmer regions of Africa, Asia, and the Americas. Zika virus typically leads only to minor disease symptoms in healthy adults. However, when a pregnant woman is infected, the virus can pass to her fetus and lead to birth defects. Children being born with a condition called microcephaly, where the head and brain are abnormally small, is the most well-known of these birth defects. Microcephaly leads to many mental handicaps and developmental problems throughout life. How Zika virus infection leads to microcephaly is not fully understood at this point of time. Zika virus infects the cells of its host and multiplies using the biological machinery that is present within these cells. To do this the virus hijacks various host proteins within these cells to utilize their functions to help the virus achieve things the virus cannot do with its own proteins. Earlier research has found a possible mechanism that could be behind microcephaly. This research found that Zika virus interacts with a host protein called ANKLE2. Naturally occurring mutations in this protein have been seen in children with microcephaly. In this project we wanted to find out if Zika virus purposefully hijacks ANKLE2 to facilitate its own replication or if this is just an accidental interaction that has no benefit for Zika virus. To do this we made cells that could no longer produce the ANKLE2 protein. We then infected these cells with Zika virus and measured the number of infectious viruses present at specific time points after adding the virus. We found that Zika viruses could not multiply as well when the ANKLE2 protein was no longer present within the cell. We tested this for liver, lung, and placental cells to ensure this was not specific to a particular cell type. In addition, we also tested this with different strains of Zika virus to ensure it was not strain specific. These results show that the presence of the ANKLE2 benefits the multiplication of Zika virus in some way. We were also curious if the ANKLE2 protein was used by relatives of Zika virus. So, we infected cells without ANKLE2 with either dengue virus or yellow fever virus and measured the number of infectious viruses after specific timepoints. We found that the multiplication of dengue virus was altered when the ANKLE2 protein was no longer present. The effect on yellow fever virus multiplication was very small though. It is important to further understand how Zika virus causes microcephaly and how these interactions might benefit the virus. As, the mosquito species that transmits Zika virus is spreading to more countries due to global warming it is becoming more important to understand microcephaly and how to manage it as a future Zika virus outbreak is very possible. And this information could help us develop possible treatments for Zika virus disease related issues.