Mapping and modeling macrophages in tuberculosis

Abstract

Immune cells polarize to diverse transcriptional and functional states to cause or resolve disease. Understanding this cellular diversity is critical to identifying new clinical interventions. Macrophages in tuberculosis granulomas are an archetype of these phenomena. Pinpointing the cellular states and features required for effective responses to vaccination or Mycobacterium tuberculosis infection remains challenging. Recent advances have dramatically increased the scale and depth of profiling transcriptional states and their pathological implications.

In this thesis, we describe several studies that collectively advance our definition of macrophages and their dynamics in tuberculosis and lung diseases more broadly. We first characterize the single-cell transcriptomic profiles of macrophages within tuberculosis granulomas from non-human primates. We introduce and apply a framework for identifying possible signaling cues contributing to these states using ex vivo-generated macrophage models. To extend these findings, we identify conserved gene programs underpinning macrophage states across other lung diseases in humans. Similarly, we then describe macrophage and other immune cell states after Bacillus Calmette–Guérin (BCG) vaccination in non-human primates and identify molecular features associated with protective responses. Lastly, we conclude by exploring how profiling and modeling ligand and genetic perturbations in macrophages can provide increased cellular and organismal understanding of potential interventions. Overall, these findings demonstrate experimental and analytical frameworks for analyzing immune cell states across biological models and inform our understanding of macrophage states associated with tuberculosis disease and vaccination.