For Salmonella and many other disease-causing bacteria that find their way into our bodies, infection begins with a poke. That’s because these bad bugs are equipped with a needle-like protein filament that punctures the outer membrane of human cells and then, like a syringe, injects dozens of toxic proteins that help them replicate.
Cammie Lesser at Massachusetts General Hospital and Harvard Medical School, Cambridge, and her colleagues are now on a mission to bioengineer strains of bacteria that don’t cause disease to make these same syringes, called type III secretion systems. The goal is to use such “good” bacteria to deliver therapeutic molecules, rather than toxins, to human cells. Their first target is the gastrointestinal tract, where they hope to knock out hard-to-beat bacterial infections or to relieve the chronic inflammation that comes with inflammatory bowel disease (IBD).
To enable the research, Lesser’s team— including Wendy Garrett of Harvard, and John Leong at Tufts University School of Medicine, Boston—received an NIH Director’s 2016 Transformative Research Award. They’re starting with a harmless strain of the bacterium Escherichia coli (E. coli) that is widely used in humans as an anti-inflammatory probiotic. If successful, the research could point the way to making relatively low-cost designer probiotics that could directly target treatment to the site of many health problems.
In 2015, Lesser showed for the first time it was possible to insert the type III secretion system of diarrhea-inducing Shigella bacteria into harmless E. coli . Secretion systems only inject proteins that include a specific “green-light” sequence. The researchers added that sequence to a muscle-related protein and demonstrated that the E. coli could inject the proteins into mammalian cells.
Lesser later realized it might be simpler and just as effective for drug delivery purposes if the good bacteria squirted therapeutic proteins into open space instead of injecting them into cells. She and her colleagues have now devised a version of their probiotic E. coli complete with a squirting secretion system.
As proof-of-concept, working with colleague Charles Shoemaker at Tufts University Cummings School of Veterinary Medicine, North Grafton, MA. they’re engineering good E. coli to produce and secrete a new class of therapeutic biomolecules known as single-domain antibodies. These antibody fragments come with the advantage of recognizing bacterial toxins or inflammatory factors with exquisite sensitivity—similar to whole antibodies, but in a much smaller package.
Their small size should make it feasible for bacteria to deliver them and, potentially, to develop a probiotic, antibody-based treatment in a pill. The next step will be to test these designer probiotics in mouse models of intestinal infection or inflammatory disease.
By the way, Lesser didn’t originally plan on studying biology or medicine at all. She’d always liked math and science, but her interest as a kid was geology. She spent summers in the western United States, studying mountain formations and dabbling in archaeology. But in her early years of college, she found her way to molecular biology and never looked back.
As a graduate and medical student in the 1980s and 1990s, she was interested in studying infectious bacteria, but ended up tinkering with the genomes of laboratory yeast. Later in her own lab, she returned to bacteria, interested in understanding how infectious bacteria manipulate their hosts. That’s how she got interested in bacterial secretion systems. Now, with the help of her colleagues, she’s found a way to bring all of that curiosity and expertise together to develop vitally needed new platforms for drug delivery.
 Engineering Escherichia coli into a protein delivery system for mammalian cells. Reeves AZ, Spears WE, Du J, Tan KY, Wagers AJ, Lesser CF. ACS Synth Biol. 2015 May 15;4(5):644-54.
Lesser Lab (Massachusetts General Hospital, Harvard Medical School, Cambridge, MA)
Wendy Garrett (T. H. Chan School of Public Health, Harvard University, Boston, MA)
Leong Lab (Tufts University, Boston)
Project Information (NIH RePorter)
NIH Director’s Transformative Research Program (Common Fund)
NIH Support: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases