Caspase-12 Increases Susceptibility to Diarrheal Diseases

Molecular microbiology researchers have found that the protease caspase-12 interferes with the ability of the cells lining the digestive tract to fight off bacterial infection.

Investigators at McGill University (Montreal, CA) studied the effect of caspase-12 on the activation of Nod genes that occurs when pathogenic bacteria attack epithelial cells and the resulting production of the antimicrobial peptides known as defensins. Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They are active against bacteria, fungi, and enveloped viruses. They consist of 15-20 amino acids including six to eight conserved cysteine residues. Cells of the immune system contain these peptides to assist in killing phagocytized bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by penetrating the microbial's cell membrane by way of electrical attraction, and once embedded, forming a pore in the membrane that allows efflux of cellular materials.

Results published in the March 13, 2008, issue of the journal Cell Host & Microbe revealed that by interfering in the cascade of protein interactions leading up to NOD activation, caspase-12 inhibited the innate immune response of the mucosal cells lining the digestive system, rendering them more susceptible to invasion by bacteria such as Escherichia coli.

"This mechanism expands our idea of immunity: it hinges upon epithelial cells, not immune cells, early on during infection,” said senior author Dr. Maya Saleh, assistant professor of microbiology and immunology at McGill University. "Furthermore, our study demonstrates that this mechanism is regulated negatively by the caspase-12 protein, meaning that this protein limits defensin production. This hampers the elimination of bacteria, which then trigger an intense inflammatory reaction manifested by various symptoms including severe diarrhea.”


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