Whitehead Scientist Identify the Single Protein Responsible for Bacterial "Comet Tails" To Infect Cells

CAMBRIDGE, Mass. — Scientists at the Whitehead Institute and the Albert Einstein College of Medicine have shown that a single surface protein called IscA is all that the bacteria Shigella flexneri needs to propel itself inside and among host cells—a characteristic that enables the organism to infect human colon cells and cause diarrhea. Eschericha coli, when engineered to express the Shigella protein, acquire the same ability to move inside and among frog egg cells. The finding has implications for understanding cancer, building vaccine delivery systems, and finding new ways to combat bacterial resistance. The results are reported in the July 3 issue of the Proceedings of the National Academy of Sciences.

Shigella are rod shaped bacteria that normally inhabit the human intestinal tract. They induce diarrhea in humans by invading and spreading through the mucus membrane of the colon. Crucial to their ability to infect and spread through the cells is their capacity to form “comet tails,” rich in the protein actin, which the bacterium co-opts from its host cells. The actin-based comet tail gives 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.

Scientists had known from analyzing Shigella mutants that the surface protein IcsA is directly involved in the interaction with the host cell cytoskeleton. They also had known that IcsA is located at one end of the organism, expressed during the growth phase, when the bacteria are dividing rapidly, and that a cleaved form of the protein is secreted by the bacteria.

In this study, scientists tested IcsA's role in conferring motility by engineering E coli to express IcsA in the absence of other Shigella gene products. The scientists found that IcsA, independent of its location, cleavage, or growth phase regulation, is sufficient to confer actin-based movement through cells.

Listeria monocytogenes, an unrelated food-borne parasite that causes meningitis and stillbirths in humans, also uses actin tails to propel itself through and among infected cells. These bacteria co-opt proteins in the cytoskeleton of infected host cells to form “comet tails.” This suggests that the tail strategy developed independently at least two different times in bacterial evolution. Whitehead Fellow Julie Theriot expects to learn a great deal about bacteria-host communication by comparing the tail-forming mechanisms in the two species.

Dr. Theriot's work is representative of a revolution in infectious disease research, stimulated in part by the emergence of multi-drug resistant strains of tuberculosis and other bacteria. There is growing awareness that altering and remodeling conventional antibiotics will not be enough to retain our advantage over disease-producing microorganisms. The race is on for new strategies to disrupt the life cycle of these clever and unpredictable foes.

One possible strategy is to block communication between bacteria and their human host cells. Dr. Theriot explains that bacteria alone do not make people sick; infection is a collaborative process that requires both an infectious agent and a responsive host cell. The comet tails are a good example. They are composed of a human protein called actin, the primary girder in the framework of the human cell cytoskeleton. 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. Dr. Theriot is identifying and characterizing these proteins and studying how they interact at the molecular level. Ultimately, she hopes to know enough about this process to stop it. 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.

Dr. Theriot's research is building a new foundation for anti-bacterial therapy and also answering basic questions about the components of the cytoskeleton in mammalian cells. For example, actin-based motility is important in many life processes, including early embryonic development and the movement of metastatic cancer cells. Dr. Theriot's work on the biochemistry and biophysics of the actin-based comet tails could shed new light on structural changes associated with normal and abnormal growth in all human tissues.