Tuberculosis (TB) is a lasting global epidemic that claims ~1.5 million human lives annually. Mycobacterium tuberculosis (Mtb) is the causative agent of TB and this bacterium establishes an infection by surviving within macrophages and manipulating the host immune response. It is the infected macrophage that orchestrates the formation of a granuloma, the hallmark pathologic lesion associated with a TB infection. Isolated within the granuloma Mtb can persist for decades sequestered away from the pressures of the host immune response. During this persistent infection Mtb must control its metabolism to efficiently utilize host-derived nutrients for survival. It is well established that Mtb's ability o process and utilize host-derived lipid nutrients during an infection is essential for bacterial survival during an infection. Additionally, recent work has revealed that Mtb not only utilizes hos lipids as a nutrient source to supply energy producing and/or biosynthetic pathways but also actively processes toxic metabolites generated during catabolism of host lipids. By understanding the host-derived nutrient metabolic pathways in Mtb we will likely identify new weaknesses to facilitate the discovery of new therapeutic strategies against this pathogen. For this project we will characterize several mutants identified in a genetic screen designed to identify novel mutants of host nutrient utilization by Mtb. Specifically, this screen allowed for te identification of suppressor mutants that are defective in processing host-derived lipid nutrients.
Aim 1 : we will phenotypically classify Mtb mutants by counter screening for growth defects on different carbon sources in vitro and prioritize the mutants based on intracellular fitness in a macrophage infection model.
Aim 2 : will biochemically categorize the catabolic and biosynthetic metabolites from the pathways perturbed in the mutants. These studies will provide novel insight into the Mtb metabolic pathways that are essential during an infection which may be targeted by new intervention strategies.
Mycobacterium tuberculosis (Mtb) is the causative agent of Tuberculosis and is responsible for approximately 1.5 million deaths annually. A key component of this disease is the ability of the bacterium to persist for long periods in the human host. The proposed research will identify the bacterial metabolic systems required for survival in vertebrate hosts.
|Lovewell, Rustin R; Sassetti, Christopher M; VanderVen, Brian C (2016) Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr Opin Microbiol 29:30-6|
|VanderVen, Brian C; Fahey, Ruth J; Lee, Wonsik et al. (2015) Novel inhibitors of cholesterol degradation in Mycobacterium tuberculosis reveal how the bacterium's metabolism is constrained by the intracellular environment. PLoS Pathog 11:e1004679|
|Russell, David G; Lee, Wonsik; Tan, Shumin et al. (2014) The Sculpting of the Mycobacterium tuberculosis Genome by Host Cell-Derived Pressures. Microbiol Spectr 2:|