A single surface protein, IcsA, is all that is needed for the bacterium Shigella flexneri to develop a "comet tail" to propel itself through host cells and spread infection, scientists have reported.
When the scientists inserted the gene for this protein into the common laboratory bacterium Escherichia coli (E. coli), the organism acquired a Shigella-like mobility. Such mobility is achieved by co-opting the human protein actin and refashioning it into a propulsion engine. The findings may have implications for combating bacterial resistance, building new vaccine delivery systems and understanding the movement of cancer cells.
The findings were reported in the July 3 issue of the Proceedings of the National Academy of Sciences by scientists at the Whitehead Institute for Biomedical Research and the Albert Einstein College of Medicine.
"Although Shigella cause dysentery throughout the world, especially in overcrowded areas with poor hygiene, the infection can be treated easily and inexpensively with existing antibiotics. The value of our finding is that it sheds light on actin-based motility, an important part of many biological processes, including early embryonic development and the movement of metastatic cancer cells," Dr. Julie Theriot, a Whitehead Fellow, said. She co-authored the paper with Dr. Marcia Goldberg, assistant professor of microbiology and immunology at the Albert Einstein College of Medicine in New York.
Shigella are rod shaped bacteria that cause diarrhea in humans by invading and spreading through the mucous membrane of the colon. Crucial to Shigella's ability to infect and spread through cells is their capacity to recruit the human protein actin, the primary girder in the framework of the human cell cytoskeleton, and reconstitute it into a "comet tail." The actin-based comet tails give the bacteria enough speed to leap from an infected cell to an uninfected neighbor, spreading infection and limiting the bacteria's exposure to disease-fighting elements of the human immune system.
Knowing its role in human life processes, scientists have long tried to find the basis for actin-based motility. Studying it without perturbing the rest of the cell's processes has been extremely difficult, leading scientists to focus on bacteria like Shigella that seem to have mastered this strategy.
In this study, Drs. Theriot and Goldberg tested IcsA's role in conferring actin-based motility by engineering E. coli to express IcsA in the absence of other Shigella gene products. "We found that the IcsA protein is sufficient to allow actin-based movement through cells, independent of its location, cleavage or growth phase regulation," Dr. Theriot said.
Another bacterium, Listeria monocytogenes-a food-borne pathogen that causes meningitis and stillbirths in humans-forms actin tails much like those seen in Shigella, but the two species are completely unrelated. "This suggests that the tail strategy developed independently at least two different times in bacterial evolution," Dr. Theriot said. She expects to learn more about bacteria-host communication by comparing the tail-forming mechanisms in the two species.
Another important implication of this study is that it points to Shigella and Listeria as possible candidates for vaccine delivery systems.
Scientists may be able to engineer Listeria or Shigella to carry HIV proteins or pieces of mycobacteria. "Because Shigella and Listeria can get into the cytoplasm of cells, their proteins can be attacked by the part of the immune system that specializes in fighting most viral infections and certain bacterial infections," Dr. Goldberg said. "With this type of response, immune cells attack the infected cells rather than just make antibodies to the virus or bacterial particles."
Dr. Goldberg added that Shigella and Listeria are also easy to manipulate and work with in the laboratory. The work on Shigella and Listeria represents a possible new direction in anti-bacterial therapy, necessitated in part by the growing problem of multi-drug resistant strains of bacteria. Scientists believe that strategies to combat these ever-changing microbes must move beyond remodeling conventional antibiotics and focus on blocking the bacterium-host cell interaction instead.
Bacteria alone do not make people sick, Dr. Theriot explained. Infection is a collaborative process that requires both an infectious agent and a responsive host cell. The comet tails are a good example. Dr. Theriot's research has shown that the formation and elongation of L. monocytogenes comet tails requires constant communication between L. monocytogenes proteins and actin-associated proteins derived from the host cell. Without their tails the bacteria would be crippled; they could not move from cell to cell to spread infection. Drugs designed specifically to block the activity of the tail-building proteins would represent an entirely new direction in medicine.
This work was funded in part by grants from the National Institutes of Health, the Pew Scholars Program in the Biomedical Sciences and the W.M. Keck Foundation of Los Angeles.
A version of this article appeared in MIT Tech Talk on July 19, 1995.