Another Reason to Monitor Your Cholesterol…Preventing Ebola Infection

 Since its most recent outbreak in 2015-2016, Ebola Virus (EBOV) infection and treatment has been a major focus of basic and translational research in virology.  A new study by Flint et al. suggests that EBOV infection mechanisms are closely tied to already elucidated mechanisms of late endosome-lysosome binding, which allows EBOV to deposit its genome into host cells. Past research established potential molecular targets for preventing this mechanism, using loss-of-function gene trapping in addition to siRNA and shRNA dependent methods. This research built off of that past work, using an unmodified version of EBOV (instead of previous used EBOV-VSV hybrids with lower infectivity) and evaluating the effects of different gene products at the DNA- level (through CRISPR methods) as opposed to the transcript level. Their results suggest that GNPTAB, which encodes N-acetylglucosamine-1- phosphate transferase α and β subunits, is a potential antiviral target for preventing or halting EBOV infection. Their experimentation knocks out the GNPTAB gene and shows a dramatic increase in viability of host cells after a set infection period (from 25% to 90% after KO). Further, restoration of this gene and its transcripts to the host cell restore EBOV infection and host cell death rates. These experiments were repeated with already existing cell lines, as well as patient isolates with GNPTAB non-functional mutations and their families. Each of these experiments showed consistent and repeatable results that resulted in significantly lower EBOV infection rates in GNPTAB-depleted cells. To propose transcript level inhibition of GNPTAB action is sufficient to prevent these serious infections, SKI-1/S1P protease activity was inhibited via small molecules. Interestingly enough, SKI/S1P is also an essential component in cholesterol storage and synthesis, which motivated past research to discover these small molecule inhibitors. Given that SKI-1/S1p proteolytically cleaves GNPTAB and in doing so allows for its proper expression, this small molecule inhibition had the potential to also prevent GNPTAB action. This inhibition was also able to recreate the increase in viability of gene deletion, and therefore, supports GNPTAB as a potential antiviral target for combatting EBOV infections in patients.

~Kyle Enriquez

Sources: https://www.nature.com/articles/s41467-018-08135-4?WT.feed_name=subjects_ebola-virus