The spirochetes are a group of bacteria that are responsible for several deadly ailments including the notorious illnesses, Lyme disease and syphilis. These organisms have developed a special mode of propulsion, whereby their flagella wrap around the cell body to power a screw-like `drilling' motion made by the entire organism. This trait is especially useful for infecting people and other animal hosts, for two reasons: (1) it keeps the flagellum close to the cell body, where it can be covered up by the bacterial outer membrane; this helps spirochetes evade the host immune system, which usually recognizes flagella with ease as a `foreign invader'; and (2) the `drilling' action is highly effective at penetrating dense materials, such as host tissue, which speeds up and otherwise facilitates infection. Despite the clear relevance for disease, many aspects of spirochete motility remain mysterious, including the precise composition and three-dimensional structure of the molecular machinery that drives it. We formed a multidisciplinary, multinational team focused on understanding the detailed structure and function of a spirochete flagellum, working with a pathogenic strain called Leptospira that causes a deadly water-borne illness called leptospirosis. We are using an integrative approach that combines advanced cryo-electron microscopy and cryo-electron tomography, X-ray crystallography, molecular microbiology and genetics techniques, to address major open questions, including: (1) why do spirochete flagella contain many distinct types of protein components when their counterparts from other bacteria need only one; (2) what is the molecular basis of a distinctive, highly coiled flagellar morphology in Leptospira ; and (3) how do these features facilitate motility? By combining complementary top-down and bottom-up strategies, our approach should shed light on spirochetal biology and pathogenesis, and unveil novel molecular targets to develop drugs and vaccines with improved efficacy. 8
Leptospira are Spirochete bacteria that cause a severe zoonotic disease, leptospirosis, using their flagella to swim and disseminate within the infected hosts. Distinct from all known flagella, the molecular structure and functional workings of the Leptospira assembly are still poorly understood. This research will reveal novel motility mechanisms associated with pathogenesis, ultimately leading to improved strategies for the treatment of leptospirosis and other spirochete diseases. 9
