Vincent & Michelle – I just finished listening to TWiM247. Thanks for such a great discussion of our recent paper in Nature Medicine. It was super! I thought I’d just add a couple of points with some clarifications on some great discussion items….
Unlike eukaryotic viruses, antibody recognition of phage capsids may not be at all neutralizing. It’s more likely that the neutralizing antibodies are recognizing the tail tip proteins that are actually in contact with the bacterial cell wall. But I think we have lots of learn about that. Nonetheless, engineering this aspect of the phage biology is something we’re interested in, as you suggested.
Incidentally, the idea of engineering these phages may seem trivial, but it’s not lambda, and it’s not E. coli! So we can do it, but only because we’ve developed all the tools for doing so, including mycobacterial recombineering, recombineering of phages (BRED), and now CRISPY-BRED (attached). All fairly straightforward, not without some effort!
The general idea of using a 3-phage cocktail and switching to another 3-phage cocktail is fine if you have lots of phages to work with. But for the NTMs, we actually have very few. So this is a challenge. And the M. abscessus variation is high, so that screening for phages to use therapeutically is not a simple task. I attached too more papers recently out in mBio. Sorry they are a bit dense, but I think they are a good description of where we are at with the microbiology.
Also in these papers is the issue that phage resistance is actually quite uncommon in M. abscessus, so cycling through the use of individual phages (to stay one step ahead of the immune response) is not unreasonable. Also covered in these papers.
Anyway, thanks a ton for such a terrific discussion, and especially all the focus on the more junior people that contributed to make it all happen. This is yet another testament to the power of strong scientific collaborations, especially between the basic scientists (my lab; with a side-project in science education tossed in) and the physicians (Keira et al).
Keep up the excellent work and stay safe!
Graham F. Hatfull
Department of Biological Sciences
University of Pittsburgh