A Locksmith & The Immune Army

djd_3136-smallThe immune system relies heavily on memory and recognition, with its success dependent on marshaling defenses against only the right infectious invaders. Scientists are finding that this memory requires a lot of moving parts, including molecules that grab pieces of bacteria and viruses, specialized cells that can determine whether those pieces are dangerous or not, and cells that attack and kill those microbes if they are ruled to be a threat. The key at each step of this complex system is specificity; if each component only binds or attacks certain types of molecules, it makes the process of remembering the correct response that much easier. As with a condo building, having the right locksmith can make all the difference.

Bacteria are largely made up of proteins and lipids, and when they first get inside a cell, the initial defense system strips them down to these parts. For proteins broken up into smaller pieces called peptides, the MHC molecules are the designated grabbers, binding the molecules and bringing them to the cell surface for recognition. But for lipids, a different group of molecules, the CD1 family, performs this task. Because lipids make up the bacterial cell wall – the critical outer barrier of the microbe – they are good, reliable candidates for jogging the immune system’s memory and initiating a response.

“It’s a really excellent way of recognizing a bacterial lipid, because they look a lot different than what they look like in us,” said Erin Adams, assistant professor of biochemistry & molecular biophysics at the University of Chicago. “If you are a bacteria, you can mutate your protein to evade the immune response and not be recognized any more, but it’s really difficult to change the structure of a lipid. If you screw it up too much, then the bacteria doesn’t survive.”

Understanding more about how these CD1 molecules function could be helpful in building better vaccines or treatments against bacteria and viruses. But the traditional scientific approach of taking a snapshot of these molecules (through the method of X-ray crystallography) was frustratingly difficult. So a multi-disciplinary team led by Louise Scharf in Adams’ laboratory set about using some molecular engineering to solve that problem, and their work was published last month in the journal Immunity.

The mission was to catch one of the CD1 family, CD1c, in the act of binding with a bacterial lipid; in this case, a component of the bacteria that causes tuberculosis called mannosyl-ß1-phosphomycoketide (MPM, for much-needed short). The protein was normally too unstable for crystallography, so Scharf and colleagues meticulously changed pieces of CD1c to create a more stable structure, without betraying the molecule’s original function.

“We did a lot of tests to make sure that the protein that we made, our Frankenstein protein, was only Frankenstein in the bits that didn’t count, the structural parts of the protein,” Adams said. “We had to keep validating along the way, step by step, to make sure we weren’t creating a monster.”

djd_3026The process was successful, and the first picture of the CD1c molecule at work was captured, revealing several surprises. The other members of the CD1 family have two pockets used to literally catch lipids by their tails, and the depth of these pockets gives them the specificity that’s so important for immune system memory. However, CD1c is a rebel; instead of pockets, it has a tunnel, and a surface groove, lending it a little more flexibility in what kinds of lipids it can grab by the tail.

Instead of only binding lipid tails that are just the right size for its pockets, CD1c’s keyhole can fit longer lipids that stick out through the “escape hatch” at the end of the tunnel, Adams said. The tunnel is also wider, enabling the molecule to catch the bulkier lipid tails of MPM. Meanwhile, the surface groove expands the versatility of CD1c, potentially allowing the molecule to capture lipo-peptides, hybrid molecules present in many pathogens.

How can this information help fight dangerous infections? Understanding the form and function of CD1c gives scientists a foundation from which to build newer, smarter vaccines, or treatments that can bolster the immune system of a person already infected with a pathogen. In the case of tuberculosis, a synthetic molecule that binds to CD1c and triggers the cascade of immune response might protect against future infections with the bacterium, Adams said.

“The idea would be to try to find something that could initiate a larger repertoire of T-cell response in people, before they are actually exposed to tuberculosis,” Adams said. “What we’re looking for as far as a vaccine is something stable and easily administered to people that would be properly presented in the right context and then recognized with just enough potency to cause the proliferation and establishment of an army.”

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Scharf, L., Li, N., Hawk, A., Garzón, D., Zhang, T., Fox, L., Kazen, A., Shah, S., Haddadian, E., & Gumperz, J. (2010). The 2.5 Å Structure of CD1c in Complex with a Mycobacterial Lipid Reveals an Open Groove Ideally Suited for Diverse Antigen Presentation Immunity, 33 (6), 853-862 DOI: 10.1016/j.immuni.2010.11.026

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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