TTHE IMMUNE The system has many weapons with which to counter incoming hostiles. But what works against one may not work against another. An intruder can take advantage of this by tricking the system into thinking that he is fighting an enemy that he is not. This buys time for that intruder to gain a foothold. That’s sneaky. Even more sneaky, however, is the approach just discovered by Ruslan Medzhitov of Yale University. As he and his colleagues report in ImmunityThey have found a bacterium that induces the immune system of its host to release compounds that it can then 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, elicit a type 2 response when type 1 would be appropriate. Dr. 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 that he was causing the body to mount an ineffective type 2 response against him, and they wanted to know how he was doing it.
To explore the matter, they grew laboratory cultures of the type of epithelial cells that line human airways and monitored their gene expression profiles when exposed to LasB, a toxic enzyme produced by the bacteria. They found that LasB activated signaling pathways that prompted epithelial cells to produce a protein called amphiregulin. This forms the base of a thick mucus that stands out to trap parasitic worms. It also recruits immune cells called eosinophils, which are experts at attacking multicellular parasites.
A type 2 error
That finding alone is interesting, because it helps explain why cystic fibrosis patients with bacterial infections often develop copious amounts of mucus in their lungs, even though this does nothing to counteract the bacteria. More intriguing, however, was what happened when the researchers tried to grow P. aeruginosa in samples of this mucus. As long as LasB was present, the bacteria not only thrived, but actually consumed the mucus. it is not only P. aeruginosa by tricking the immune system into giving an inappropriate response, it is also feeding off the result. And to make matters worse, Dr. Medzhitov also found that all this immunological manipulation makes the surrounding tissues allergy-prone.
Allergic reactions are essentially exaggerated and inappropriate type 2 immune responses. Therefore, the researchers wondered if the reactions created by LasB could cause long-lasting allergies to develop. To find out, they sprayed infected mice 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 thing with some mice genetically engineered so that they lacked the ability to produce amphiregulin when exposed to LasB.
They theorized that, in the absence of worms, inflamed epithelial tissues in normal mice might 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. In contrast, amphiregulin-free mice showed little.
These discoveries, fascinating in themselves, also pave the way for new approaches to treating infections in people with cystic fibrosis. Furthermore, if one insect has evolved a way to milk the immune system, it is very likely that others have as well. Thus alerted, researchers will be attentive to similar cases. ■
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