How does Musashi 1 enhance Zika virus replication?

Viruses spread by insects cause some of the most important emerging human diseases. As the range of their insect hosts expands, increasing populations are becoming at risk to infection. An outbreak of Zika virus, spread by mosquitos, in Central and South America in 2015/2016 was accompanied by an increase in microcephaly cases in new-born babies. Microcephaly is a condition where the head circumference is smaller than usual and is typically associated with developmental defects. A causal link between Zika virus infection and defects in neural cell and brain development has since been firmly established with neural stem cells being particularly susceptible to infection, and destruction, by the virus. Recent evidence has also demonstrated a link between Zika virus infection and long-term cognitive dysfunction, suggesting that both adults and foetuses are at risk of debilitating disease following exposure. Like other viruses, Zika virus can only replicate once it enters a host cell. The virus genome consists of a single piece of nucleic acid called RNA that is replicated and packaged into new virus particles before being released to spread the infection. Virus replication can be positively and negatively affected by proteins present in the infected cell. Many of these are RNA-binding proteins that interact directly with the viral genome. We recently demonstrated that a host protein called Musashi-1 strongly enhances Zika virus replication. Musashi-1 is known to affect the expression of specific proteins by binding directly to their corresponding RNAs. High levels of Musashi-1 are present in the neural precursor cells that are highly susceptible to Zika virus infection. A mutation in Musashi-1 that affects its ability to interact with RNA is also linked to congenital microcephaly, independent of Zika virus infection. Together, our previous findings support the hypothesis that the presence of Musashi-1 in Zika virus infected cells may contribute to the neural destruction and associated brain development defects observed in affected individuals. In this project we will examine the interplay between Musashi-1 and Zika virus using cutting-edge techniques. We will focus on three main questions: 1) At what stage of the Zika virus replication cycle does Musashi-1 exert its effect and can mutation of Musashi-1 binding sites in the Zika virus RNA affect its ability to reproduce in neuronal cells? 2) Does sequestration of Musashi-1 through binding to the Zika virus RNA disrupt the normal function of Musashi-1 in neuronal cell development? 3) Does Musashi-1 promote the ability of Zika virus to replicate in neural stem cells in mini brains? From this work we expect to advance our knowledge of how the presence of a protein that normally promotes neural cell development can make cells more permissive for Zika virus replication. This research can also reveal novel aspects of basic neurodevelopmental processes. Understanding how Musashi-1 enhances Zika virus replication may ultimately help us to develop safer vaccines with reduced risk of damaging side effects.