Wanted: Dead or Alive

It would be very useful for the immune system to be able to discriminate between live and dead bacteria.

Well, that's pretty obvious.

Immunologists have long known that live bacteria induce different, and better, adaptive immune responses than dead bacteria. Again, it may seem obvious, but is hard to reconcile with current thinking about how adaptive, or antigen-specific, immune responses develop. Robust adaptive immune responses need two things: the antigen that makes antigen-specific T and B cells expand, and inflammatory signals, which tell the immune system that something wrong or dangerous is around and that its okay to try and eliminate the sources of the antigens they recognize.

(This is not the whole story, but its a good starting point, and the whole point of this blog is to try and understand the point of immunology and not to get hung up on details.)

Anyway, seminal and beautiful work by many people, primarily Charles Janeway and Ruslan Medzhitov (you'll definitely hear more about him here, I really enjoy reading what he writes), found that those inflammatory signals could be triggered by specific components of microbes, called "patterns". In other words, when the immune system ( the innate immune system, have I mentioned how strange I find these categorizations? I digress) sees a molecule X, which is made by almost all bacteria of a certain kind, it responds because X is a pattern, characteristic of "bad" bacteria. So if you combine foreign antigens and pattern X, you should get nice robust responses to the antigens because you have both antigens and inflammation.

And you do get beautiful, strong responses to antigens this way. The only problem is that dead bacteria usually retain their patterns, like X. So there must be something else that sets live bacteria apart from their dead counterparts, something other than pattern X.

In a simple, elegant study published in Nature, Julie Blander's lab at Mount Sinai found a possible candidate-a pattern that is characteristic of bacterial life, a vita-PAMP they call it ( not my favorite term, but...). They show that ribonucleic acid, or RNA is rapidly lost from bacteria when they are killed, and that if you just add RNA back to dead bacteria, they become as good at inducing strong immune responses as live bacteria. Specifically, they found that messenger RNA (mRNA), so called because they carry the information coded by a gene in a message that is "translated" into a protein, is a vita-PAMP.

What is so strange, and so cool, about their findings is that they found that all bacteria had vita-PAMPs and the ability to induce certain immune responses. Not just pathogenic, or harmful bateria, but al bacteria, including the billions that live in our digestive tracts and at our mucosal surfaces, our commensal families. Why then do we not explode in a mass of inflammation and immune responses-after all we share body space with billions of bacteria? Is it because of strict specialization and compartmentalization: are the cells that recognize vita-PAMPs far away from our natural bacterial buddies, so that their detecting vita-PAMPs is a sign that bacteria are where they have no business being? Or do our immune systems keep responding to vita-PAMPs at a low level, and so get de-sensitized? Or, to get a little fanciful, is it good for us to keep responding to some levels of vita-PAMPs all the time-keep the immune muscles warm and in tone?

Much food for thought. And the nice thing? All this comes from such a simple question and an old observation-someone just asked "But, why?"

(Kind of like-why do ultra-tired babies cry their heads off instead of going to sleep? It's so obvious, you're tired, go to sleep. Don't sit up in bed, throw all your cuddly sleep toys out of your crib and howl to the high heavens. Apparently it is not that obvious. Sigh.)