Genetic control of immune response to Listeria infection

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DESCRIPTION (provided by applicant): Despite steady improvements in public health, factors ranging from centralized food manufacturing to potential bioterrorism keep the risk of exposure to foodborne pathogens high. In the human population, differences in immune response to infection are determined by the unique allelic combinations of each individual. Our long term goal is to understand the extent of variation in immune function and to determine how this variation affects the course and outcome of infection. Listeria monocytogenes is a gram positive bacterium which is both an important human pathogen and a proven tool to study immune function. It is however difficult to study the genetic control of sensitivity to L. monocytogenes infection in human populations. Inbred strains of mice, on the other hand, are genetically tractable and display a wide range of sensitivities to L monocytogenes infection. For our studies of the genetic control of susceptibility to L. monocytogenes infection, we selected the sensitive, BALB/cByJ, and resistant, C57BL/6ByJ, strains of mice. Our analysis of the survival of F2 progeny of these strains following intravenous infection with L monocytogenes identified two major quantitative trait loci (QTLs), Listrl on chromosome 5 and Listr2 on chromosome 13. Our current goal is to perform positional cloning of the genes controlling the differential response to L monocytogenes infection contained in these loci. To achieve this we will: 1. Fine map the L. monocytogenes susceptibility loci. We will perform extensive genetic and phenotypic examination of our congenic mouse lines, decrease the size of the loci and define their boundaries. 2. Identify candidate L. monocytogenes sensitivity genes Polymorphic genes that are likely to control differential sensitivity to L. monocytogenes infection will be identified by a combination of a positional cloning and a hypothesis driven strategies 3. Establish the role of polymorphic genes in control of L. monocytogenes infection. We will establish the definitive role of CXCL11 in control of L monocytogenes infection using transgenic approaches. In addition we will create the framework for analysis of additional candidates.