Manipulation of host cell peroxisomes by the bacterial pathogen Legionella

About This Grant

PROJECT SUMMARY Peroxisomes are essential organelles that play pivotal roles in diverse biochemical pathways, from lipid metabolism and homeostasis to reactive oxygen detoxification. Peroxisome activities are intimately linked with other organelles, both functionally, coordinating metabolic pathways, and physically, through membrane contact sites that allow direct transport of metabolites between sub-cellular compartments. Recently, peroxisomes have been recognized for acting as signaling platforms, with key roles in immunity. Thus, a pathogen’s ability to modulate peroxisome biology could have profound impacts on numerous host cellular processes. However, the role of peroxisomes in bacterial pathogenesis remains largely unexplored. Recent findings indicate that bacterial pathogens exploit peroxisome biology to subvert host defenses. Many intracellular bacterial pathogens reside within membrane-bound compartments, shielding the bacteria against recognition and killing by host immune surveillance pathways. Maintaining the integrity of these replication vacuoles is critical for pathogen survival and virulence. Recently, we discovered an unprecedented link between bacterial pathogens and peroxisomes in which mutations that render peroxisomes metabolically inactive restrict replication vacuole expansion, induce vacuole rupture and limit bacterial replication. In the case of Legionella, we found that this pathogen actively manipulates host peroxisomes, altering the relative abundance of peroxisome metabolic enzymes, and recruiting peroxisomes to its replication vacuole. These processes are dependent on the bacterium’s Type IV secretion system, implicating Legionella secreted effector proteins in peroxisome modulation. However, the effectors involved remain unknown. The goal of this proposal is to elucidate how Legionella manipulates host peroxisome biology and to define the role of peroxisomes in Legionella pathogenesis. We will identify and characterize the bacterial effectors responsible for altering peroxisome metabolic programming and location, providing critical insight into the virulence strategies employed by Legionella. By uncovering novel effector functions and host targets, this work will advance the molecular understanding of bacterial pathogenesis and host cell manipulation. Moreover, this research will address a critical gap in our understanding of how bacterial pathogens exploit host organelles to establish infection. Given the emerging evidence that other intracellular bacterial pathogens - Salmonella, Mycobacterium and Chlamydia – also exploit peroxisomes, our studies are expected to reveal broadly relevant virulence strategies.