Scientists at the Biozentrum of the University of Basel say they have found a protein family that plays a central role in the battle against Salmonella within cells. Their study (“Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases”) is published in Nature.

Salmonella bacteria use macrophages as host cells to ensure their survival and to be able to spread within the body. Their survival strategy is to nestle into a vacuole within the cytoplasm of a macrophage, hiding there and multiplying. While they are hidden there, the immune cells cannot detect the bacteria and fight them.

The macrophages in which the Salmonella hide, however, have also developed a strategy to unmask the disguise of the bacterium and uncover its hiding place. The research group led by Petr Broz, Ph.D., at the Biozentrum discovered a protein family called interferon-induced GTPases in host cells invaded by Salmonella.

“They are responsible for destroying the hiding place of the pathogen and to initiate the immune response of the cell,” explains Etienne Meunier, Ph.D., first author of the publication.

Once the hiding place has been discovered, GTPases are transported to the vacuole and destabilize its membrane. The bacteria are left behind unprotected in the cytoplasm where their surface molecules are easily recognized by the intracellular defense.

“We report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the noncanonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria,” wrote the investigators. “We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor.”

Dr. Broz believes the findings of his team will enable a better understanding of immune cell strategies and to perhaps model this system for further research in the future. The deeper understanding of the immune response of our cells also paves the way for new approaches in using drugs to support the body’s fight against pathogens, he adds.

The scientists’ next step will be to investigate how cells detect the hiding place of the bacteria, the vacuole in the cytoplasm of the macrophages, and what initiates the recruitment of GTPases to the vacuole.

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