Analysis of pathogen determinants recognized by the hypervariable immune receptor Dscam
Background: To mount an immune response, host organisms must first recognize the pathogen with which they are infected. The first line of defense against pathogen infection in animals is provided through the innate immune response. Many aspects of this response are conserved in invertebrates making the fruitfly Drosophila with its sophisticated genetic tools a model of choice. The fundamental knowledge obtained about the innate immune response in fruitflies has even been recognized by a Nobel prize.
Recently, the Drosophila Down syndrome cell adhesion molecule (Dscam) gene has been shown to act as pattern recognition receptor in phagocytosis, in addition to its role in neuronal wiring [1, 2]. The Dscam gene generates through alternative splicing over 36’000 different isoforms by inclusion of a single exon in each of the variable regions (Fig 1). Intriguingly, the splicing pattern of Dscam changes upon infection to express isoforms with a higher affinity towards the pathogen in mosquitoes . We anticipate that Dscam splicing is also altered in Drosophila upon pathogen exposure to dramatically increase inclusion of specific isoforms. We currently don’t know the identity of the pathogen molecules recognized by Dscam, or how pathogens impact on adapting Dscam alternative splicing for pathogen recognition and if the same mechanism is also used in the human innate immune response.
1) Identify pathogens and conditions that induce preferential inclusion of single variable exons in Drosophila Dscam
2) Determine pathogen components that are recognized by Dscam and impact on its alternative splicing
3) Determine the mechanism(s) through which pathogens impact on alternative splicing regulation
Project description: From a wide array of pathogens available from the Institute of Microbiology and Infection at the University of Birmingham we will first identify those that induce inclusion of a narrow range of exons in the three variable regions as they are indicative of high affinity interactions. For this analysis we developed highly efficient Molecular Biology tools, including high throughput sequencing for efficient analysis .
Once we have obtained a broader choice of pathogens we will identify the bacterial molecules impacting on Dscam alternative splicing and determine if they bind to Dscam using genetic, molecular and biochemical approaches.
Alternative splicing is thought to provide a major mechanism for adaptation of cell function to changing environments, e.g. during infection. The Dscam splicing pattern is initially established in a predefined ratios, but probabilistically at a cellular level [4, 5]. We will establish a GFP-based Dscam alternative splicing reporter to identify the pathways, how pathogens lead to adaptive changes in alternative splicing during an innate immune response.
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 Watson FL et al (2005) Science 309: 1874.
 Hemani Y and Soller M (2012) Biochem Soc Trans 40: 804.
 Dong Y et al (2006) PLoS Biology 4: e229.
 Haussmann IU et al. (2015) submitted.
 Miura SK et al (2013) Cell 155:1166.
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