How does Zika virus replicate?
Zika virus hijacks a key protein implicated in brain development for its own replication.
Researchers led by Associate Professor Priya Shah at the University of California, Davis (CA, USA), have discovered that Zika virus (ZIKV) hijacks a host protein essential for brain development for its own replication purposes in humans. Because ZIKV can cross the placenta, it can have serious consequences for pregnant individuals; however, it isn’t entirely clear what’s happening on a subcellular level during infection. And, of course, understanding how it infects and replicates within humans is key to developing new vaccines against it.
Mosquito-borne ZIKV is a positive-sense single-stranded RNA orthoflavivirus, which relies on hijacking host proteins to replicate. Previous Drosophila research from Shah’s lab has demonstrated that a ZIKV protein – called NS4A – interacts with a host-cell protein – called ANKLE2. Although ANKLE2 is a key protein in brain development, it is also found throughout the body. In the current study, Shah’s team took their research one step further to investigate how ANKLE2 interacts with ZIKV in human cells.
To investigate ANKLE2’s interactions with NS4A, the researchers utilized HEK293T cells expressing FLAG affinity-tagged fusions of ANKLE2 and two control groups of cells expressing GFP-FLAG and ANKLE1-FLAG. These cell groups contributed a general, non-specific control as well as provided a control to distinguish between intrinsic localization of ANKLE proteins and unique ANKLE2 localization. These cell lines were then infected with three different strains of ZIKV. Using microscopy, they investigated the interaction between FLAG-tagged ANKLE2 and NS4A.
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Following ZIKV infection, they found that ANKLE2 distribution became concentrated and colocalized with NS4A, while ANKLE1 distribution did not. ANKLE2 colocalized with NS4A in clustered pockets around the endoplasmic reticulum, forming viral production factories that can hide from the immune system. Knocking out the ANKLE2 gene reduced ZIKV’s ability to replicate.
“Zika and related viruses have evolved strategies to hide themselves in these replication pockets to avoid detection. We believe that ANKLE2 is hijacked to help facilitate this process, and without it the pockets don’t form as well and the immune system can keep virus replication in check,” first author Adam Fishburn reported.
Further investigations demonstrated that ANKLE2 plays a role in ZIKV infection of mosquito cells as well as humans. Additionally, NS4A proteins in other related mosquito-borne viruses – such as dengue virus and yellow fever virus – also interact with ANKLE2, potentially highlighting the importance of the NS4A–ANKLE2 interaction in viral replication.
By gaining a greater insight into the NS4A–ANKLE2 interaction and its role in ZIKV replication, the researchers are hopeful that new drugs and vaccines could be developed to target this interaction.
