UC Berkeley

Mycobacterium tuberculosis, the causative agent of tuberculosis, is responsible for an enormous burden of morbidity and mortality worldwide, and is responsible for nearly 2 million deaths annually. As a pathogen, M. tuberculosis is extraordinarily successful, infecting an estimated 2 billion people worldwide. M. tuberculosis is able to thrive in macrophages, an immune cell type that specializes in eating and killing bacteria. Despite the remarkable capabilities of M. tuberculosis to infect and persist in humans, the large majority of immunocompetent people are able to successfully control infection, and there is great interest in understanding what characterizes a successful immune response to M. tuberculosis infection. One of the key molecules in the immune response to M. tuberculosis is the cytokine Interferon gamma (IFN-γ), which is primarily produced by CD4+ T Cells during the adaptive response to infection. IFN-γ is thought to activate macrophages, allowing them to kill M. tuberculosis. Within this dissertation, I describe novel insights into the effects IFN-γ has on macrophages during M. tuberculosis infection.

My dissertation work has focused primarily on two proteins, Hypoxia Inducible Factor 1 alpha (HIF-1α) and Inducible Nitric Oxide Synthase (iNOS), which are both activated by IFN-γ in macrophages during M. tuberculosis infection. First I demonstrate that HIF-1α activation during M. tuberculosis infection is IFN-γ dependent, and that this activation of HIF-1α is required for successful control of infection both in macrophages and in mice, and that HIF-1α regulates a variety of immune responses including aerobic glycolysis, eicosanoid production, inflammatory cytokine production, and nitric oxide production. Next, I explore the signaling roles of nitric oxide during M. tuberculosis infection. In the context of M. tuberculosis infection, nitric oxide has been assumed to primarily be a direct bactericidal effector. However, nitric oxide has well documented signaling roles in a variety of other contexts. Here, I show that nitric oxide plays key signaling roles during IFN-γ activation of M. tuberculosis infected macrophages. I find that nitric oxide is strongly anti-inflammatory via inhibition of NF-kB signaling, while at the same time nitric oxide activates antimicrobial responses via stabilization of HIF-1α.