Grant: Operating Grant

Guts are major entry sites for numerous pathogens and gut cells perform essential barrier functions against invading microbes. Thus, it is essential to ensure that gut cell proliferation keeps pace with the rate at which a microbial assault damages gut cells. A failure to do so may result in catastrophic intestinal breaches and chronic disease states. A groundbreaking series of studies uncovered a striking evolutionary conservation of the formation and cellular architecture of mammalian and fly guts. Furthermore, the regulatory circuits that control immune responses in flies tend to be highly conserved throughout evolution. Thus, the genetically accessible fruitfly serves as an ideal tool to study gut cell proliferation during intestinal infections. We recently developed a novel experimental method that allowed us to rapidly survey the entire fruitfly genome for genes that control the activation of immune responses. In this study, we showed that detection of foreign microbes results in the production of a secreted molecule, Pvf2, which drives the cellular proliferation of numerous cell types. More recently, we showed that Pvf2 is specifically expressed in the gut during infection. Overlapping studies revealed that Pvf2 controls the proliferation of damaged gut cells. These observations led us to propose that bacterial damage of gut cells triggers the intestinal production of Pvf2, which drives a compensatory cellular proliferation in the gut. Such proliferative responses are essential to ensure the maintenance of an intestinal barrier to invading pathogens. Remarkably, the mouse equivalent of Pvf2 appears to perform related functions in the control of cellular proliferation in the gut. Thus, it appears that Pvf2 may perform evolutionarily conserved roles in the formation and maintenance of animal guts. In this research project, we will perform a comprehensive characterization of the role of gut cell proliferation in fly immune responses to pathogenic microbes