There is a growing awareness of the essential role that the natural microbiota play in the development and maintenance of health. This awareness has led to recognition of the importance of understanding how humans and other animals maintain beneficial bacteria in persistent associations with their tissues. There are thousands of such bacterial species associated with the epithelial surfaces of our skin, mouths, gut tracts and urogenital systems, yet we know very little about how they maintain a stable association with us throughout our lives. This knowledge is vital to designing safe and effective therapeutic measures against pathogens, as we must understand the factors that create stabile relationships between hosts and their essential microbial partners before we treat disease. The complexity of mammalian host-microbe interactions has made their study challenging, and has led to the use of simplified model associations such as gnotobiotic (germ-free) animals. Another, complementing, approach has been the use of natural animal models in which only a single bacterium is associated with a specific tissue, as in the symbiosis between Vibrio fischeri and its host squid. These bacteria associate for months with the epithelial surfaces of the host, but recent work has revealed that the symbionts induce a daily effacement of the tissue's surface, which then recovers within hours. This natural cycle of disruption and recovery provides an excellent opportunity to define the signaling events underlying the daily remodeling of an epithelial surface in long-term contact with its bacteria, and discover how this communication creates a dynamic stability that leads to health. To reach this goal we propose to define the cellular, biochemical and genetic events that drive the bacteria-induced effacement of the host epithelium, and its subsequent recovery, by: (i) understanding the cellular events underlying the daily cycle of tissue remodeling, (ii) determining the role of unique symbiont characters in signaling epithelial effacement, and (iii) identifying conserved toxin-like effectors that act in the effacement/recovery cycle PUBLIC HEALTH RELEVANCE: There is a growing awareness of the essential role that the natural microbiota play in the development and maintenance of health. This awareness has led to a recognition of the importance of understanding how humans and other animals maintain beneficial bacteria in persistent associations with their tissues. We will investigate a natural bacterial association to define the signaling events that underlie a symbiont-induced daily remodeling of the host's tissues that leads to a healthy persistent interaction.