SpoVG and PlzA Regulation of Lyme Disease Spirochete Infection Processes

Bacterial infections require that the pathogen accurately produce essential factors at appropriate levels during each stage of infection processes. Understanding how bacteria control levels of their proteins in response to cues from their hosts provides important insights on microbial infectious properties. Such knowledge can also reveal new targets for improved preventative and curative therapies. The Lyme disease spirochete, Borrelia burgdorferi, survives in nature through a cycle of infecting vertebrates and ticks. The CDC calculates that there are approximately 300,000 new cases of human Lyme disease in the USA each year. B. burgdorferi can persistently infect immunocompetent humans and other mammals for many years. Failure to treat Lyme disease promptly and adequately can result in persistent debilitating effects or, sometimes, death. The most significant problems occur with long-term infections, which may require extensive periods of antibiotic treatment. In order to better treat B. burgdorferi infections, it is critical to develop a more thorough understanding of B. burgdorferi biology, including the mechanisms by which the spirochete controls production of virulence factors. We discovered that a borrelial protein, SpoVG, binds with specificity and high affinity to DNA and RNA. Deletion of spoVG significantly impaired B. burgdorferi¡¦s ability to colonize ticks and be transmitted from ticks to mammals. Dysregulation of spoVG transcription caused significant changes in bacterial physiology. We also found that SpoVG physically interacts with another B. burgdorferi protein, PlzA, the Lyme spirochete¡¦s sole cdi- GMP-binding protein. PlzA is also a site-specific nucleic acid-binding protein, and ƒ´plzA mutants are defective in their infectivity. Among the regulated targets we identified for SpoVG and PlzA is the antigenicallyvariable VlsE surface protein, which is essential for persistent B. burgdorferi infection. The planned studies will simultaneously investigate SpoVG and PlzA, as well as the effects of c-di-GMP on their functions. The combined efforts of the investigators¡¦ laboratories will yield a comprehensive view of the mechanisms through which B. burgdorferi controls production of these critical regulatory factors, and deep insights on how SpoVG, PlzA, and c-di-GMP regulate VlsE and other virulence-associated proteins. In addition, many other pathogenic bacteria produce homologs of SpoVG, and our observations on B. burgdorferi SpoVG bear similarities with the protein¡¦s known effects in other bacterial pathogens. To date, little is known about SpoVG affects virulence and physiology in any bacterial species. The interactions we discovered between SpoVG and PlzA raise the possibilities that other bacteria also control SpoVG function through c-di-GMP-binding proteins. Results of the planned investigations will provide useful insights on the regulatory mechanisms and infectious properties of numerous important human pathogens.