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Campylobacter jejuni is the leading cause of bacterial derived gastroenteritis worldwide, accounting for an estimated 400-500 million cases annually, with a projected 2.4 million diagnosed and undiagnosed cases in the United States. The most common source of infection is through the ingestion of raw or undercooked chicken meat, which is often contaminated with Campylobacter from the chicken gastrointestinal tract during the processing of meat products. <p/>Due to the importance of C. jejuni commensalism to human infection, much interest lies in understanding the factors of the bacterium that promote colonization of the chicken gastrointestinal tract. Regardless of the importance, only one previous study attempted to take a genome-wide approach to identify these factors, but was limited in its scope due to technical disadvantages of their protocol. Here we propose the use of an incredibly sensitive novel screening technology, termed INSeq, which utilizes deep sequencing as a means of quantifying the relative abundance of each mutant within an output pool. We believe that the use of this new technology will provide us with the most comprehensive, to date, accounting of factors involved in commensalism of the chicken gastrointestinal tract. Also, we intend to screen for small molecule inhibitors of a previously identified colonization factor in an attempt to identify those that may be efficacious in reducing the numbers of commensal C. jejuni in the chicken gastrointestinal tract. <p/>The two goals are outlined in the specific aims: Specific aim 1: Identify mechanisms of C. jejuni that influence commensal colonization of the chicken gastrointestinal tract using a deep-sequencing-based mutagenesis approach. Specific aim 2: Identify small molecule inhibitors of a known C. jejuni colonization factor. These aims, while independent, will work synergistically since novel factors identified from specific aim 1 can be subjected to the same screen proposed in specific aim 2. Such a design is not only likely to yield a number of new colonization factors, but also a variety of compounds that may aid in the study of C. jejuni colonization factors and reducing the burden of C. jejuni within the chicken gastrointestinal tract.
PUBLIC HEALTH RELEVANCE: Campylobacter jejuni is the leading cause of bacterial-derived gastroenteritis worldwide. The bacterium most often infects humans in the developed world following the consumption of undercooked meat that was contaminated after dissemination of C. jejuni from the chicken gastrointestinal tract. The proposed fellowship study has two aims: i) use genome-based methods to identify mechanisms used by C. jejuni to colonize the chicken gastrointestinal tract and ii) identify potential inhibitors of colonization by screening for small molecules that reduce expression of a previously identified colonization factor. Both of these aims have the goal of controlling human campylobacteriosis either through development of infection control protocols or the isolation of novel anti-Campylobacter therapeutic compounds.