Innate Immunity

The innate immune system is the evolutionarily conserved arm of our immune system and can therefore be successfully studied in model organisms. The fruit fly Drosophila is currently the most useful non-mammalian model for studies of cellular differentiation and innate immunity. Antimicrobial peptides (AMPs) are crucial effector molecules that prevent infection in epithelial and mucosal linings, and combat infections once established. The long-term goalof our research is to understand how innate immunity is regulated, and to study important links between host-pathogen interaction, cellular proliferation and differentiation at the level of signal transduction and gene regulation.
 

The role of POU transcription factors in innate immunity

We have previously demonstrated the importance of NF-kB/Rel and GATA transcription factors for inducible expression of AMP genes in response to infection. More recently, we isolated cDNAs for 10 putative Drosophila regulators in a yeast double interaction screen. Among the candidate regulators, three encoded the Drosophila POU transcription factors Dfr/Vvl, Pdm1/nub and Pdm2/miti. POU factors constitute a subgroup of the Hox/homeo domain class of transcription factors, and are known to be crucial regulators of cellular proliferation, differentiation and migration in both flies and humans.

We have shown that Dfr/Vvl is highly expressed in many immunocompetent tissues and that it drives expression of the CecA1 gene in the male reproductive organs by binding to an ejaculatory duct enhancer. Furthermore, Dfr/Vvl and the homeodomain protein Caudal (Cad) activate transcription synergistically via this enhancer. Recent work has revealed that also Pdm1 and Pdm2 regulate the expression of immune defense genes. Our hypothesis is that POU transcription factors act together with other regulators in a combinatorial fashion to control immune gene expression in a gene-, tissue-, and sex-specific manner, thus promoting a first-line of defense against infection. The future goals are to characterize how POU transcription factors regulate expression of antimicrobial peptide genes and epithelial immunity in Drosophila and in human cells.

 

Host-fungal pathogen interactions

Fungal infections are of increasing concern to humans, especially for immunocompromised patients, including those receiving chemotherapy. Candida albicans causes severe infections in immuncompromised individuals, and are also lethal to Drosophila. In collaboration with the lab of Per Ljungdahl, WGI, SU, we have developed Drosophila as a mini-host model for studies of fungal virulence, and shown that C. albicans mutants in the SPS sensing pathway are less virulent to wild-type Drosophila. This relatively cheap and quick assay system is used for in vivo virulence screens, and for evaluating the specific roles of the different components of the C. albicans SPS signaling system. We also plan to refine this model to be able to examine the efficacy of antifungal agents, with the aim of conducting in vivo screens with large chemical libraries to identify lead compounds with antifungal activity.