Tissue damage is one of the most severe perturbations for a living organism. Tissue damage may occur upon infection with pathogens or by injury. Animals need to trigger multiple pathways at the cellular, tissue, and organismal levels to overcome the harmful impact of such insults. Over an evolutionary scale, animals have acquired the capacity to recognize signals called damage-associated molecular patterns (DAMPs). DAMPs activate specific pathways involved in the repair or inflammation. Numerous DAMPs have been identified in animals; however, the molecular mechanisms triggered by DAMPs and the cellular responses to these molecules are not well understood.
In our recent work, we attempted to study the host (Drosophila) in response to injury. First, we analyzed the gene expression profile of blood cells at the injury site. Remarkably, this work revealed a dramatic upregulation of the JAK/STAT cytokine upd-3 (IL-6 like) and the Toll signalling pathway that has been chiefly associated with pathogen infection. We showed that intracellular accumulation of hydrogen peroxide in hemocytes is critical for upd-3 induction. How does hydrogen peroxide gets imported into hemocytes? Moreover, we revealed that the diffusion of hydrogen peroxide occurs with the help of a channel protein Prip. And, in the absence of Prip, cytokine upd-3 production is impaired. Because of the similarity in the pathways that get activated by clean injury, or upon infection with pathogen/s, we asked if injury-based hemocyte activation can train the immune response for subsequent infection. Strikingly, injured flies are better protected from infection with a bacterium like Enterococcus faecalis. We further show that this training is dependent on the production of reactive oxygen species (ROS) at the site of a sterile injury.
Beyond studying the mechanisms of injury-based response in flies, the other theme that fascinates me is how bacterial infection or injury leads to stem cell proliferation in the fly gut. Earlier work has shown the importance of JAK/STAT signalling in pathogen/injury-induced stem cell proliferation. This work also established that hemocytes act as a messenger between the gut and the distant wounded region. My ongoing work focuses on how hemocytes signal to distant tissues like the gut on wounding and regulate stem-cell divisions. We found flies that are deficient in producing upd3 in hemocytes fail to proliferate intestinal stem-cell (ISC). And this causes increased susceptibility to injury. Currently, I am looking at the molecular changes that occur in the gut in response to wounding and are essential for host survival.
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