UC Berkeley

The bacterial pathogen Mycobacterium tuberculosis has been a major contributor to mortality throughout human history and is uniquely difficult to treat with available antibiotics. M. tuberculosis is currently recognized as the leading cause of death due to a single infectious agent in humans worldwide, killing between 1.5 and 2 million people every year. While disease burden is largely concentrated in poor communities without access to healthcare and pharmaceuticals, a recent rise in multi-drug resistant strains threatens all of us. This looming public health crisis heightens the need for new therapies to be developed. It also highlights the need to better understand bacterial lifestyles and molecular dynamics of host-pathogen interaction.

M. tuberculosis lives inside the phagosome of host macrophages, a hostile compartment deadly to most phagocytosed microbes. Even sequestered inside the phagosome, M. tuberculosis has evolved mechanisms to manipulate the host and developed the ability to acquire factors required for survival and replication. My research has focused on the fundamental yet perplexing questions of what carbon sources M. tuberculosis accesses and survives upon during infection, and conversely how host cells alter their lipid metabolism in response to infection. Previously, M. tuberculosis was thought to manipulate macrophages to form lipid droplets as a readily available store of carbon to support bacterial growth. However, my work demonstrated that macrophages produce lipid droplets in support of host immune responses, as part of a novel signaling pathway involving IFN-γ, HIF-1α, and HIG2. I also found that bacteria are incapable of acquiring lipids from macrophage lipid droplets and that instead bacteria acquire lipids from an unknown source intracellularly. These findings inspired screens in an arrayed transposon library to identify prokaryotic genes important for lipid import and survival during infection. I present the discovery of three novel genes required for import of fatty acids and formation of prokaryotic lipid droplets during infection. Separately, I present a new randomly barcoded transposon library that will enable high-throughput selection assays to define gene fitness and function.