From my guest column at the Biophysical Society Blog.
The first full day of BPS 2015 began a little bit late for me, with my west coast body insisting that 8 am was 5 am and not at all an appropriate time to be getting out of bed. The “New and Notable” Symposium began at 10:45am which was quite a bit more palatable to my jet lag addled brain. This symposium was very well attended, with most of the talks being standing room only. This is unsurprising as the speakers were selected by the program committee from over 100 preeminent researchers nominated by the society’s membership. The talks ranged from a study attempting to mimic membrane channels with chopped up single-walled carbon nanotubes to a structural study of the activation and sensitization of ionotropic receptors.
Getting to hear about many different topics of research is one of the advantages of a big meeting like BPS, and I was very please to listen to Gaya Amarasinghe’s talk on the mechanisms through which the Ebola virus evades the immune system. Everyone knows about Ebola, and it’s also no secret that it’s remarkably well-equipped to combat our immune systems. This talk went from a 30,000 foot view of the recent international outbreak of Ebola all the way to elucidating the detailed molecular interactions of one protein-protein interaction between host and pathogen.
The defense mechanism described involved VP24 (one out of only a handful of proteins encoded by Ebola) and the nature of its antagonistic effect on STAT1, a signaling protein triggered by the innate immune system’s recognition of double stranded RNA. Upon detecting the viral infection and producing interferon, the cell’s next step is to get STAT1 to the nucleus by means of the KPNA nuclear transporter so it can up-regulate transcription of anti-viral genes. Here’s where Ebola’s incredibly clever VP24 comes in. VP24 binds to the KPNA nuclear transporter in just the right way to prevent STAT1’s binding and nuclear transport, but not in a way that prevents most other functions of this multifunctional nuclear transporter that are useful for viral replication.
Professor Amarasinghe himself smiled as he acknowledged he was jumping through 6 graduate student years of work in a slide or two as he presented the detailed nature of this binding interaction. His structure-guided mutation study showed that the binding interface of KPNA and VP24 is a unique non-classical nuclear localization signal used only by STAT1. The binding of VP24 did not effect the transport of classical nuclear localization signal-containing cargo. Thus Ebola is accomplishing a targeted strike of the nuclear transport that will set of the cell’s alarms, while preserving the machinery needed for its own replication. Furthermore since the binding site of STAT1 is integral to immune cells proper functioning, it’s a target that can not easily be evaded by mutations in the host without deleterious effects.
So we get it, Ebola is very good at what it does. Luckily Professor Amarasinghe went on to show that the efficacy of this defense mechanism does reveal a possible chink in Ebola’s considerable armor. Just as targeting the STAT1 binding site of KPNA made the host unable to respond to the virus through mutation, drugging the KPNA binding site of VP24 could be a viable approach that would be difficult for Ebola to evade through viral mutation. In fact, the inhibitory effect on STAT1 transport to the nucleus was extremely sensitive to mutations in this region, suggesting pharmacological targeting could be a robust approach to resensitize Ebola to the innate immune system.
As a researcher working in therapeutic screening and design for pathogens, this type of structural and biological insight makes my job so much easier, and it was a pleasure to see the type of thought process and experimental plans (and prodigious time!) that go into making these types of discoveries.