The role of TOR kinase signaling in responses to bacterial infection
Creators: name: Deshpande, Rujuta Shailesh
Publisher: name: Cumming School of Medicine
Year: 2021
Subjects: subject: TOR
subject: metabolism
subject: infection
subject: Education--Sciences
subject: Biology--Molecular

description: Animals in their natural ecology are often exposed to environmental stressors (e.g., starvation, extreme temperature, hypoxia, pathogens) that can affect their physiology, development, and lifespan. An important question in biology is how animals sense these stresses and, in response, adapt their metabolism to maintain homeostasis and survival. In some cases, specific tissues function as stress sensors to control whole body adaptive responses. One well-studied example is the Drosophila intestine. Along with performing absorptive, digestive, and endocrine functions, the intestine also functions as both a stress sensor and signaling hub, to regulate systemic metabolic changes. Upon encountering enteric pathogenic bacteria, Drosophila adults mount organism-wide immune and physiological responses in order to provide infection resistance and promote tolerance. The Drosophila intestine controls both local and systemic anti-bacterial immune responses. Recent work shows that the gut also signals to other tissues to control whole-body metabolic changes to promote infection tolerance. However, the mechanisms underlying how these stress sensing tissues link the stressors such as infection to metabolic adaptations is not well understood. In my thesis, I show that one way by which the fly intestine mediates these adaptive metabolic responses is via induction of target-of-rapamycin (TOR) kinase signaling. TOR is a well-established regulator of metabolism that has classically been shown to be activated by growth cues and suppressed by stress conditions. Interestingly however, I found a rapid increase in TOR activity in the fly gut in response to enteric gram-negative bacterial infection stress, independent of the classic innate immune response. Furthermore, I showed that blocking this TOR induction reduced survival upon infection. My data suggest that these protective effects of gut TOR signaling on organismal survival may be mediated through altered whole-body lipid metabolism. Lipid stores are an important metabolic fuel source. They can be synthesized and stored in specific tissues and then mobilized, transported to other tissues, and used to fuel metabolism, particularly in stress conditions. Infection leads to transient loss of lipids which is perhaps needed to fuel the immune response. This transient loss and restoration of lipids was further exacerbated by TOR inhibition. Infection also induced TOR dependent systemic expression of transcription factors and enzymes that promote de novo lipid biogenesis, indicating one way by which TOR inhibits excess lipid loss is by promoting de novo lipid synthesis upon infection. Moreover, genetic upregulation of intestinal TOR was sufficient to induce the expression of some of these lipid synthesis genes. In addition to systemic effects, enteric infection also induced TOR dependent local intestinal lipolysis and beta oxidation genes, and endocrine signaling peptides which have previously been implicated in whole body lipid homeostasis. I propose a model in which induction of intestinal TOR signaling is an infection stress sensor that leads to local intestinal changes such as lipolysis and secretion of signaling peptides, which perhaps non autonomously signal to the rest of the animal to upregulate lipid synthesis upon infection. TOR upregulation represents a host adaptive response to counteract infection mediated loss of whole-body lipid stores in order to promote survival. While only a handful of studies have investigated a role for TOR signaling upon infection with varying results, my thesis supports the idea of TOR activity being beneficial for the host to survive enteric infection. I propose TOR signaling as a link between infection and metabolic adaptations which contributes to infection tolerance.