Functional and evolutionary genomics of host adaptation

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Pathogens and their hosts continuously engage in a relentless and often deadly struggle mediated and modulated by diverse suites of virulence factors on the pathogen side, and surveillance and defense sys-tems on the host side. Characterizing these factors is central to understanding and controlling disease. This proposal describes an ambitious, novel, and robust means to identify and characterize what are arguably the two most significant factors influencing disease and defense: pathogen-associated molecular patterns (PAMPs) and type III secreted effector proteins (T3SEs). PAMPs are microbial factors that are recognized by receptors on plant and animal cells, and which induce immune or defense responses. T3SEs are bacterial proteins injected into host cells to disrupt the induction of these immune responses. We have developed a PAMP screen which has already dramatically increased our understanding of the breadth and nature of these important molecules. The proposed work will further refine our inventory of PAMPs, clearly identify the suite of host defense receptors that recognize each PAMP, trace the defense signaling networks to determine their variety, specificity, and interdependence, determine how sensitive these defense signaling pathways are to disruption by T3SEs, and then assess the role that natural variation among PAMP alleles plays in influencing host specific interactions. Importantly, this study will provide a very general framework for studying PAMPs in any system, and specifically proposes to develop a general tool for these studies. The PAMPs identified in this study have the potential to be used as novel antimicrobial agents as they can be deployed in a range of different formats, and induce immunity in very specific ways. The study will take advantage of the hard work already done by co-evolutionary process to reveal the 'weak links' in defense signaling networks - those points in the defense network most vulnerable to pathogen attack. We will identify the bacterial virulence proteins that target these weak links. The net result of these studies will be a vastly enhanced understanding of the factors that influence innate immunity - factors that immediately impact our health, our food supply, and our environment.