Drug Discovery Opinion

The identification of host genes that are exploited by bacteria and viruses could lead to new therapeutic targets but gene inactivation by mutation is inefficient in (diploid) mammalian somatic cells because when one copy is inactivated, the second copy usually remains active and continues to provide protein. Genetic experiments are typically carried out in model systems such as yeast cells which can exist in a haploid state with only one copy of each gene, but researchers at the Whitehead Institute for Biomedical Research have now developed an assay system based on a human cell line, KBM7, that exists in a haploid state except for chromosome 8, which is present in two copies. The team inactivated individual genes by insertional mutagenesis and then assessed the ability of bacterial toxins or viruses to kill the cells. A variety of pathogenic bacteria secrete potent toxins known as cytolethal distending toxins (CDTs) which cause cytotoxicity by inducing breaks in cellular DNA, resulting in arrest of the cell cycle. By identifying mutagenized KBM7 cells that were resistant to CDT from E. Coli, the gene encoding sphingomyelin synthase I and a gene encoding a putative G protein-coupled receptor were shown to cause susceptibility to CDTs. Examination of mutant cells resistant to influenza virus A infection revealed an enzyme and a transporter protein involved in sialic acid biochemistry as key to susceptibility. Because native anthrax toxin is not cytotoxic for KBM7 cells, the researchers used a modified toxin to probe mutagenized cells and found that a previously uncharacterised component of the dipthamide biosynthetic pathway confers sensitivity to toxin-mediated cell death.

As well as allowing the identification of genes involved in susceptibility to infection by bacteria and viruses, the mutagenized KBM7 cells could be used to study other disease-associated molecular networks where a distinct phenotype exists.

The study is published in Science.

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