If you were going to design the perfect immune system, what would you do? This question is often posed to beginning immunology students, and the best answer may be so obvious that it doesn't occur to most. The best immune system is one that prevent pathogens from ever gaining access to your squishy bits in the first place.
And so we have barriers - lots of them. Unfortunately, the best barriers are not always practical. Plants have rigid cell walls that are almost impervious to pathogens, but plants don't need to walk around. We trade that in for skin and that does pretty well, but it has limitations. We need to be able to consume tons of nutrients to fuel our metabolism, and those nutrients need to be absorbed into our bloodstream. Being permeable to nutrients and water also allows pathogens a back-door (no pun here - move on) for bacteria and viruses to get past the gate-keepers.
The epithelial cells that line our guts provide a pretty good physical barrier themselves, but they're no match for pathogens. Instead, they rely on a number of chemical barriers - proteins and other molecules that can kill or repel bacteria without harming your own cells. One of the most abundant of these so-called anti microbial peptides is human Î²-defensin1 (hBD-1), but there's just one problem: it kinda sucks at killing bacteria.
This has puzzled scientists for a long time. There are a number of different defensins, and most of them are potent microbicides, but you can dump loads of Î²-defensin1 on bacteria and they'll mostly shrug it off. Why would the most abundant defensin in the gut be so terrible at, you know, defending?
It turns out, those scientists forgot one tiny little detail: your colon is not like the laboratory.
A disulfide bond is a chemical bridge formed between two parts of a protein chain. In the oxidizing environment present in most of our bodies (and in solutions in the lab), these disulfide bonds are very stable, and help form the shape of the protein.
But the colon is almost devoid of oxygen, and is a reducing environment. This causes those disulfide bridges to break apart, allowing the protein to unfold:
Schroeder et. al. showed that in it's reduced, stretched out form (the form that should actually be present in the gut) human Î²-defensin1 is actually really good at killing bacteria. They grew bacteria on plates with little spots of either hBD1 or hBD3 (which was known to be good at killing bacteria) and measured how large an area could be kept sterile (the defensins diffuse out so at the edges they're at a lower concentration). On the left, you see what happens under normal conditions - hBD1 (black bars) suck at inhibiting bacterial growth.
But when you add the chemical DTT, you reduce the disulfide bonds and voila! hBD-1 starts to kick ass. hBD3 actually gets worse at killing - probably because it depends on its disulfide bridges being intact.
With hindsight, I'm surprised it took so long for people to figure this out. But this just goes to show you, sometimes the obvious answer can be staring you in the face, and you won't even know it.
Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, Buchner J, Schaller M, Stange EF, & Wehkamp J (2011). Reduction of disulphide bonds unmasks potent antimicrobial activity of human Î²-defensin 1. Nature, 469 (7330), 419-23 PMID: 21248850
Okay, look, I'm starting to have nightmares wherein I'm Catherine Bates and you and Heather have lost control of your car on a highway....
Okay, to be real, what you've written is incredibly cool. The thing is, even if I can't practice the real chemistry involved...I can remember leo says ger. And I can understand that a membrane in an aerobic condition will react differently than a membrane(or antimicrobial peptide) in an anerobic condition....
you guys stretch my limits which is very, very, very cool...and just pushes me harder....
Thanx for passing on the info....
That is definitely on the top of my 2011 list for ZOMG glamor paper out of that? I WISH I'D THOUGHT OF IT/SOOOOOOOO obvious in hindsight.
@ Mike - I have no idea what that first sentence means, but I'm glad you enjoyed the post :-)
@ Becca - Seriously.
Interesting post, pretty pics. Nice work!
I was busy getting my science by the pint last night. This led to a poorly constructed reference. Kathy Bates starred in the movie Misery. She was writer (James Caan) number 1 fan. She was also a nurse who kept him prisoner after a car wreck so that he could provide her with ongoing stories...as long as she wanted. Famous for its hobbling scene. I used to read a lot of Steven King, but the supposed horror movies based on his book generally didn't frighten me. The hobbling scene scared the living hell out of me.
Hi Kevin -
I'd love to hear more about the specific mechanisms by which hBD-1 kills pathogens. Also, if you are in the 'ins' territory, a post about resolvins or alarmins would be pretty cool.
I love the way the stretched out form of the hBD1 looks like a dragon, suddenly awake.
well it was a really interesting piece ..........i was searching for answer to why defensins are still not so very successful as therapeutics even after years of toiling........and i got some answer to it .......anyways can anyone suggest new area of work in defensin .......!