THE IMMUNE The system has many weapons with which to oppose hostile invaders. But what works against one may not be effective against another. An intruder can take advantage of this by tricking the system into thinking they are fighting an enemy that they are not. This gives this intruder time to entrench himself. That’s sneaky. Even sneakier, though, is the approach newly discovered by Ruslan Medzhitov of Yale University. As he and his colleagues report in Immunitythey discovered a bacterium that induces its host’s immune system to release compounds it can feed on.
Mammalian immune systems have two modes of attack. Type 1 is used against bacteria and viruses; type-2 against multicellular parasites such as worms. Some invading bacteria, however, provoke a type 2 response when type 1 would be appropriate. The Doctor. Medzhitov decided to take a closer look.
He and his colleagues studied the behavior of Pseudomonas aeruginosa, a bacterium that causes persistent infections in people with cystic fibrosis. They suspected it was causing the body to mount an ineffective Type 2 response against it and wanted to know how it was doing it.
To explore the issue, they grew laboratory cultures of the types of epithelial cells that line human airways and monitored their gene expression profiles when exposed to LasB, a toxic enzyme produced by the bacterium. They found that LasB activated the signaling pathways that led epithelial cells to produce a protein called amphiregulin. This forms the basis of a thick mucus that excels at capturing parasitic worms. It also recruits immune cells called eosinophils, which are adept at attacking multicellular parasites.
A type 2 error
This finding in itself is interesting because it helps explain why cystic fibrosis patients with bacterial infections often develop copious mucus in their lungs, even though it does nothing to fight the bacteria. More intriguing, however, was what happened when the researchers tried to P. aeruginosa in samples of this mucus. As long as LasB was present, the bacteria not only thrived, but actually consumed the mucus. It’s not only P. aeruginosa tricking the immune system into an inappropriate response, is also feeding off the result. And to make matters even worse, Dr. Medzhitov also found that all this immunological manipulation makes surrounding tissues prone to allergies.
Allergic reactions are essentially exaggerated and inappropriate type 2 immune responses. The researchers therefore wondered whether the reactions created by LasB could cause the development of lasting allergies. To find out, they sprayed mice infected with P. aeruginosa with egg white protein (often used as an experimental allergen) on the first and seventh days of a four-week experiment. As a control, they did the same with some mice genetically modified to not have the ability to produce amphiregulin when exposed to LasB.
They theorized that, in the absence of worms, inflamed epithelial tissues in normal mice could identify the egg white protein as an intruder. This is exactly what happened. When injected with a small amount of egg white protein two and three weeks after the start of the experiment, the normal mice showed a strong allergic response to it. In contrast, mice lacking amphiregulin showed little.
These findings, fascinating in their own right, also pave the way for new approaches to treating infections in patients with cystic fibrosis. Also, if an insect has developed a way of milking the immune system, chances are good that others have too. Thus alerted, researchers will be on the lookout for similar cases. ■
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