Mechanisms of host protection during infection via the mitochondrial unfolded protein response

Project Summary Mitochondria multitask various functions such as generating vast amounts of cellular energy and regulating cell survival. Owing to their numerous cellular functions, mitochondria are often targeted by pathogens as a means to promote infection. Indeed, pathogenic microbes use various means to subvert mitochondrial function in order

to survive and establish residence in their new host environment. In response to this targeted attack, mitochondria execute various mechanisms to counter the growing infection. This includes the activation of the mitochondrial unfolded protein response (UPRmt), a stress signaling pathway that helps mitigate dysfunction to

mitochondria through transcriptional adaptation. The UPRmt stimulates mitochondrial recovery by promoting mitochondrial proteostasis, reactive oxygen species detoxification, and metabolic adaptation, among others. Critically, the UPRmt also elicits an innate immune response as an antimicrobial strategy to fight infection and

promote host survival. Consistently, loss of the UPRmt renders animals more susceptible to bacterial infection while, conversely, priming animals prior to infection increases host survival times. The coupling of innate immunity/antimicrobial defense with the UPRmt is intuitive when considering how often mitochondria are targeted

during infection. Here, we will continue to explore the fundamental question of how the UPRmt acts as a host defense mechanism during infection. Our proposal will address three broad questions: What is the role of diet and nutrient sensing in the regulation of the UPRmt during infection? How does microbial metabolism

impact the UPRmt and host survival during infection? What role does the UPRmt play in the mammalian immune system to protect the host from infection? In addition to leveraging the powerful genetics of C. elegans to dissect these intricate questions, we will implement mouse models of infection that, combined, will yield important new

and exciting insights into the UPRmt as a host antibacterial defense mechanism. Considering the significant rise of infections by antibiotic resistant bacteria, new alternative clinical interventions may be necessary. Understanding how the UPRmt provides protection during infection, therefore, will not only lead to conceptual

advances in the field of host-pathogen interactions, but may hold therapeutic value as well.