Grant: Project Grant

Mycobacterium tuberculosis (Mtb) causes the devastating lung disease tuberculosis (TB). Nearly two million people die from TB annually. Mtb infects and grows inside macrophages, a type of white blood cell present in the lungs of patients. Within these host cells, the bacteria are hidden from the human immune response and are protected from drug therapy, thus creating challenges for anti-TB drug discovery. With the increasing prevalence of multi-drug and extensively drug resistant tuberculosis worldwide, there is a pressing need for new approaches to combat TB. In this research project, we will study how a very exciting, recently discovered phenomenon, called "protein phase separation", helps Mtb survive within human macrophages. Phase separation is a localized clustering of a protein into a microscopic liquid- like "droplet". More specifically, we will investigate how intracellular signaling processes control the phase separation of a transporter protein that is used by Mtb to build its protective cell wall. These processes, which lead to the chemical modification of the transporter with phosphate groups, allow Mtb to sense environmental stimuli and mount appropriate responses for survival in human cells. We will also investigate the underlying molecular mechanisms by which phase separation occurs and how it changes the function of the transporter protein. Our research will yield new fundamental information about protein regulation in bacteria such as Mtb. This may also lead to the discovery of previously unrecognized cellular processes amenable for anti-TB drug intervention.