9 research outputs found
Examining Early Interactions between Innate Airway Resident Immune Cells and Mtb-specific Factors during Pulmonary Infection with Mycobacterium tuberculosis
Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent in the world today, infecting roughly one quarter of humans. Despite this, the mechanisms of early pathogenesis and host protective innate immune responses remain poorly understood and uncharacterized.
Lung resident Alveolar Macrophages (AMs) are the first host contact with Mtb bacilli after inhalation and are thus key mediators of the early pulmonary immune response. AMs are generally believed to reside entirely in the airway, but it was recently demonstrated that they have the capacity to egress and enter into granulomas during pulmonary infection with hypervirulent Mtb. Furthermore, we found that airway and non-airway AMs display distinct transcriptional profiles that suggest differential effector functions based on compartmental localization. The variety of effector function pathways expressed by non-airway AMs are primarily mediated by NF-kB signaling and are indicative of an M1 activation phenotype, which shifts the classic paradigm of AMs as permissive reservoirs for Mtb replication.
In the current work, we examine the host and Mtb factors/signals that modulate these compartmentally distinct AM effector functions and how these specific interactions determine protective or detrimental outcomes for the host. We examine the various functions that AMs contribute to the early immune response, focusing on migration from the airway, cellular interactions with epithelial or recruited immune cells, Mtb phagocytosis and killing, and inflammatory cytokine production. We also examine how specific Mtb cell wall lipid factors that mediate drug resistance and virulence can modulate these AM effector functions, thus skewing the host immune response
Mycobacterium tuberculosis infection drives a type I IFN signature in lung lymphocytes
Mycobacterium tuberculosis (Mtb) infects 25% of the world\u27s population and causes tuberculosis (TB), which is a leading cause of death globally. A clear understanding of the dynamics of immune response at the cellular level is crucial to design better strategies to control TB. We use the single-cell RNA sequencing approach on lung lymphocytes derived from healthy and Mtb-infected mice. Our results show the enrichment of the type I IFN signature among the lymphoid cell clusters, as well as heat shock responses in natural killer (NK) cells from Mtb-infected mice lungs. We identify Ly6A as a lymphoid cell activation marker and validate its upregulation in activated lymphoid cells following infection. The cross-analysis of the type I IFN signature in human TB-infected peripheral blood samples further validates our results. These findings contribute toward understanding and characterizing the transcriptional parameters at a single-cell depth in a highly relevant and reproducible mouse model of TB
Formation of lung inducible bronchus associated lymphoid tissue is regulated by Mycobacterium tuberculosis expressed determinants
Friend or Foe: The Protective and Pathological Roles of Inducible Bronchus-Associated Lymphoid Tissue in Pulmonary Diseases
Monocyte progenitors give rise to multinucleated giant cells
The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche. Multinucleated giant cells characterize granuloma formation in mycobacterial infections. Here the authors identify monocyte precursors with distinct immunological and metabolic properties as a source of the granuloma multinucleated giant cell compartment