UC Berkeley

A hallmark of all pathogens is an ability to acquire nutrients from hosts. In order to do this, pathogens must overcome both the tight regulation of host nutrients and the host defense mechanisms deployed to protect these nutrients.

In the introductory chapter of this dissertation, I begin with a discussion of innate immunity. I discuss the now appreciated view of the innate immune system as a sensor of patterns of pathogenesis. I then argue, based on our studies in Legionella pneumophila, that nutrient acquisition by microbes is a pattern of pathogenesis.

In chapter two, I provide experimental evidence that nutrient acquisition is a pattern of pathogenesis. I discuss my work describing how L. pneumophila alters a key metabolic signaling pathway, the mechanistic target of rapamycin complex 1 (mTORC1), in order to free amino acids for nutrition. Using an effector screen, I identified two groups of L. pneumophila Dot-dependent substrates that have opposing consequences on mTORC1. I showed that a family of Legionella glucosyltranferases, Lgt1-3, activate mTORC1 via translation inhibition, resulting in release of host amino acids. These amino acids activate mTORC1 but do so in a counterproductive way: stimulation of mTORC1 leads to the initiation of translation, which consumes the amino acids meant for L. pneumophila. To counter this, L. pneumophila also secretes the SidE family, which inhibits mTORC1 by directly inhibiting the Rag small-GTPases that are required for mTORC1-dependent amino acid sensing. The SidE effectors blind mTORC1 to the amino acids newly freed by the Lgt family. The net result of this battery of SidE and Lgt effectors is to enable L. pneumophila to manipulate the host into liberating amino acids for bacterial consumption.

I then close with a perspective chapter that describes the additional questions my work has given rise to and the state of the bacterial molecular pathogenicity field as a whole.