Another step forward in the battle against bacterial infections

Feb 12 2006

Bacterial infections can strike anyone, and they can sometimes be fatal. Because more and more bacteria are becoming resistant to the pre-eminent remedy; antibiotics; the search for new remedies against bacterial infections is in high gear. Research by scientists from the Flanders Interuniversity Institute for Biotechnology (VIB) connected to Ghent University shows that certain mice, by nature, can withstand particular bacterial infections.

Elucidation of the biological process that underlies this natural ability offers perspectives for the development of new therapeutics.

Most of the time, our body can overcome bacterial infections. Only a limited number of bacteria can make us sick, but sometimes they can be fatal. In the US, about 200,000 people die from bacterial infections each year. Normally, our natural immune system bars bacteria from entering our body, or it renders them harmless. The aggressiveness of the bacteria, our general state of health, and the speed with which our immune system reacts determine whether or not we become sick after contact with a bacterium.

Upon contact with a bacterium, or a bacterial component, the immune system springs into action. One such component of the bacterial cell wall is LPS. The binding of LPS with its specific receptor in our immune system - TLR4 - initiates a long series of reactions that bring on an inflammation, which eliminates the bacteria from our body. Of course, this chain of reactions is strictly controlled, because excessive inflammation can lead to lethal shock.

Tina Mahieu and her colleagues from the research group led by Claude Libert are working with mice that are not susceptible to toxic LPS. The VIB researchers have discovered the mechanism behind this insensitivity.

One of the steps in the process of inflammation following contact with LPS is a profuse production of type 1 interferons. These proteins play an important role in the regulation of immunity. The Ghent researchers administered 10 times the lethal dose of LPS to the mutant mice, without deadly consequences. This finding could not be attributed to an alteration in TLR4, but to a reduced production of type 1 interferons. To verify this, Mahieu and her colleagues administered these interferons preventatively to the mice - which made the animals susceptible to LPS once again. Thus, this research shows that the mice are no longer able to produce large quantities of type 1 interferons - with the consequence that an inflammation fails to arise, demonstrating the importance of type 1 interferons to the inflammation process. On the other hand, the mice produce just enough interferons to activate the immune system against the bacteria, so that the mice are protected against bacterial infections.

The results of this research are very relevant to the quest for new therapeutics for bacterial infections. The mutant mice display a combination of important characteristics: they are resistant to LPS, but they still recognize and destroy pathogens. The limited quantity of type 1 interferons enables the mice to cope with a lethal shock resulting from inflammation, but this small quantity also ensures that immunity is preserved. A next step in combating bacterial infections is to uncover the mechanism behind this reduced production.