Interesting finding! Thanks for sharing this article. Let us know if there are any further proceedings on this finding!

And yes, commenting works fine now, thanks!

Part of it is that to ask the question properly it would often be helpful, if not essential, to look at infections in an animal rather than just in tissue culture; otherwise you might not be able to tell whether something is genuinely dominant in an authentic immune response. As I’ve harped on a number of times, it’s not always easy to move into animal contexts.

Another problem is interpreting “blindness”. The ectromelia story here is actually a great example. There’s an easily-measured, apparently functional immune response to ectromelia; superficially, there’s no indication that the immune system is blind to ectromelia. But when Samuelsson et al. delivered an inactivated virus to the mouse, they actually picked up a greater response — the opposite of what you’d expect — and they interpreted this (probably correctly) as evidence that there is a component to the response that functional ectromelia shuts down. But just looking at the virus, how could you tell that the system is blinded? You probably can’t, so looking for dominance hierarchies is very tough.

wouldn’t any kind of ‘dirt’ be expected to have the same effect? Freunds adjuvans, e.g.?

In general yes, and I really wish they had included that for a control (if I had peer-reviewed the paper I would have asked for it). But my guess is that adding most passive adjuvants wouldn’t have worked as well, because the activation would be in the wrong place — the local cells but not those that ectromelia infected. By delivering the adjuvant as another poxvirus it activated the appropriate cells; and probably the proper direction of the response, if that makes a difference (which it probably does).

But we don’t know that, and I wish we did. Injecting the mice with Freunds’ would have been a great experiment.

By the way, are your comments going through correctly now?

If I understand your point correctly, in the present case the ectromelia virus does present epitopes on MHC1 but there is no immune response because the virus prevents the danger signal – which MVA provides. If this is true, wouldn’t any kind of ‘dirt’ be expected to have the same effect? Freunds adjuvans, e.g.?

It doesn’t change your point, but I think the concept is that MVA signals both through TLR9 and through a non-TLR9 pathway. Ectromelia apparently blocks the second pathway, but not TLR9 signaling. MVA stimulates TLR9, which wouldn’t much alter the response to ectromelia, but also stimulates a second, unknown, pathway. It’s the second pathway that ectromelia presumably blocks. It is still surprising that the blockade is apparently not dominant (one reason the paper caught my eye, of course), but I don’t think there’s enough known about the unknown pathway or the unknown mechanism of blockade to understand why.

From a more bioinformatical point of view, it is interesting to speculate how a Bcl2-fold protein goes about preventing TLR9 signal transduction. The parallels to IL1b signaling (also downregulated by a Bcl2-fold) suggests an action at the TIR level.