Many virulent bacteria deploy tiny needle-and-syringe-like structures known as secretion systems to inject proteins directly into mammalian cells. Now researchers have engineered one such system from a pathogenic bacterium into a harmless lab strain of Escherichia coli. These engineered bacteria synthesized a muscle protein and squirted it directly into cultured human cells (ACS Synth. Biol. 2015, DOI: 10.1021/acssynbio.5b00002).
Such bacteria could deliver therapeutic proteins to cells within the body, says Cammie F. Lesser, a microbiologist at Massachusetts General Hospital, in Boston. Because proteins on the surface of bacteria bind to specific tissue types, bacterial systems offer a way to target treatments to diseased cells. Previously, scientists had tried to exploit secretion systems in pathogenic bacteria by tweaking those disease-causing strains to make them less virulent. But such attenuated pathogens could still pose risks to patients, particularly if they have compromised immune systems.
In this study, Lesser and her colleagues turned to the type III secretion system in Shigella flexneri, a gram-negative pathogen that causes diarrhea. The team transferred all those genes into E. coli, a closely related species, to make a functional secretion system.
Secretion systems only inject proteins that include a specific amino acid sequence that marks them for export. So the researchers identified a 50-amino-acid-long sequence that included the signature sequence and linked it to the gene for a mammalian-muscle-related protein known as MyoD. When the secretion system and the tagged MyoD protein were manufactured in E. coli, the bacteria successfully injected this protein into human cancer cells (HeLa cells) in culture.
Lesser and her colleagues are taking the next step toward therapies. Currently they are engineering bacteria that can deliver anti-inflammatory proteins to treat inflammatory bowel disease.