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A battlefield inside the macrophage

Rabbit fever, deer fly fever or tularemia – these are only some of the names for one and the same serious infectious disease. It is caused by a highly contagious bacterium which invades the cells of the immune system and replicates within them. Researchers at the Biozentrum of the University of Basel has discovered that so-called guanylate-binding proteins bind to these intracellular pathogens and destroy them, so activating the defense machinery. The findings have been recently published in “Nature Immunology”.

17 March 2015

Who is smarter, who has the most sophisticated methods at their disposal or the best hide-away? This is the decisive question – also in the fight between pathogens and host cells. The infection biologist Petr Broz, Professor at the Biozentrum of the University of Basel, studies such dramatic battles at the molecular level. Together with researchers from the INSERM in Lyon, he has discovered that the macrophages of the immune system defend against bacterial invaders aided by guanylate-binding proteins (GBP).

Macrophages put up a fight

Francisella novicida is a bacterium with a clever strategy. This pathogen is difficult to detect for the immune system. Therefore, it can easily invade scavenger cells, called macrophages, and multiply inside the cells. “As few as ten bacteria are enough to cause an infection, which can lead to death in half the cases if left untreated”, says Dr. Etienne Meunier, the first author of this study. “As rodents are the main host, it is luckily rare for humans to become infected.” This makes the bacterium particularly suitable for studying the host’s defense mechanisms. In their study, Etienne Meunier and Petr Broz demonstrated that the GBPs in macrophages attach to the invading pathogens and destroy them. In contrast, in cells unable to produce these proteins, hundreds of bacteria accumulate, eventually severely affecting the surrounding, healthy tissue.

“In principle, the GBP proteins have a dual action”, explains Petr Broz. “They kill the bacteria and thus prevent bacterial growth within the cell. The DNA released from dying bacteria leads to activation of a signaling complex, the inflammasome, which initiates the death of the host cell.” This in turn activates new immune cells, which should impede the further proliferation of the bacteria. The GBP proteins are a very effective weapon in the fight against Francisella novicida. The crucial requirement for their success is, however, the preceding detection of the bacterium by specific receptors of the host cell and the production of cytokines. This first step is fundamental for the production of the GBPs which initiate the immune response.

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