Thread by @AudeBer

Stoked to report in @nature the discovery of prokaryotic viperins, which naturally produce diverse anti-viral molecules !

After providing us with antibiotics, bacteria might become sources of novel anti-viral drugs. (1/9)
nature.com/articles/s4158…

Viperin is an important immune protein in animals. In humans, it has broad antiviral activity against DNA and RNA viruses.
In 2018, this great paper showed that viperin inhibits the replication of viruses by producing ddhCTP, an RNA chain terminator.
nature.com/articles/s4158…

@Soreklab, our story with viperins started reading that paper and thinking « how cool would it be if such things existed in bacteria ».

So we looked in 40 000 bacterial genomes , and to our big surprise we did find bacterial homologs of the human viperin. We named them pVips.

Do these pVips (prokaryotic viperins) have the same function as the human viperin ?

We took ~60 pVips from diverse prokaryotes, cloned them in E. coli and challenged them with phages. Bingo, half of them provided anti-viral activity ! (3/9)

Using a phylogenetic analysis, we show the eukaryotic viperin has originated from a clade of prokaryotic viperins.

So we tried and cloned the human viperin in E. coli, the human gene protected against bacterial viruses ! (4/9)

We knew the human viperin produces ddhCTP. However our pVips sequences are much more diverse. Does the sequence diversity reflect chemical diversity ?

We ran LC-MS experiments on cell lysates and show that pVips produce ddhCTP AND ddhUTP AND ddhGTP.

Our results suggest that pVips produce new types of anti-viral molecules which, to the best of our knowledge, were not observed before in nature.

@HelenaShomar, N. Tal and M. Rosenberg from Pantheon Biosc. purified some pVips and confirmed these results in vitro. (6/9)

Finally, we developed a genetic reporting system and showed that pVips protect against T7 phage infection by inhibiting viral polymerase-dependent transcription, implying an anti-viral mechanism of action similar to the animal viperin. (7/9)

Several compounds discovered in this study are currently being tested on human viruses !

Our results show that anti-phage systems could be the source of novel anti-viral molecules. Maybe pVips are one of many systems which produce anti-viral molecules. Let’s catch some more.

A huge thanks to all the people who helped this fantastic scientific adventure and in particular R. Sorek for the guidance, freedom, creativity @AdiMillman the magician bioinformatician @gaofir and @GilAmitai for the crazy brainstorms and @HelenaShomar for the bioenginnering.

Thank you for staying until the end. I love to share this story so get in touch if you have questions and/or would like me to give seminars. Else, I have an online talk available on youtube :) .
Hope to see you soon for more science !