Citation

Humans and Mycobacterium tuberculosis (Mtb) have been co-evolving for tens of
thousands of years. Although Mtb remains the deadliest bacterial infection globally, most exposed
individuals control the infection either through clearance or containment and never develop
disease. While a quarter of the entire human population has been exposed to Mtb, how a
contained Mtb infection (CMTB) alters the biology of the host remains poorly understood. The
beginning of this dissertation investigates how CMTB alters immune responses in a mouse model.
CMTB rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol
challenge and also protects against heterologous challenges with Listeria monocytogenes or
metastatic melanoma. Protection is associated with activation of alveolar macrophages, the first
cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung
parenchyma. RNA sequencing, ex vivo functional assays, and in vivo infections demonstrate that
CMTB reconfigures tissue resident alveolar macrophages via exposure to low-grade interferon γ,
a type II interferon (IFN). These studies demonstrate that under certain circumstances, the
continuous interaction of the immune system with Mtb is beneficial to the host by maintaining
elevated innate immune responses.

To better understand the molecular interface between macrophages and Mtb, we turn to
a more tractable in vitro model of Mtb infection. Metabolic reprogramming powers and polarizes
macrophage functions, but the nature and regulation of this response during infection with
pathogens remain controversial. We characterize the metabolic and transcriptional responses of
murine macrophages to Mtb in order to disentangle the underlying mechanisms. We find that type
I IFN signaling correlates with the decreased glycolysis and mitochondrial damage that is induced
by live, but not killed, Mtb. Macrophages lacking the type I IFN receptor maintain glycolytic flux
and mitochondrial function during Mtb infection in vitro and, importantly, in vivo. IFNβ itself
restrains the glycolytic shift of inflammatory macrophages and initiates mitochondrial stress. We
confirm that type I IFN acts upstream of mitochondrial damage using macrophages lacking the
protein STING. We suggest that a type I IFN – mitochondrial feedback loop controls macrophage
responses to mycobacteria and that this could contribute to pathogenesis across a range of
diseases.
Overall, this dissertation provides new insights into the interface between the immune
system and Mtb at both the organismal and molecular scales. The evidence of beneficial effects
of CMTB on organismal health raises many questions about how the immune system responds
to contained or latent Mtb. We posit that extending the molecular mechanisms controlling the
macrophage metabolic response described here will be a critical first step in addressing these
questions