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CD11cHi monocyte-derived macrophages expressing CD38, CD14, and ABCA1 are the dominant niche for Mycobacterium tuberculosis

ABSTRACT: During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis mice were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived macrophages compared to uninfected cells. CD14, CD38, and Abca1 “triple positive” (TP) cells had incomparably high infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP+ macrophages became the dominant niche occupied by M. tuberculosis long-term. Defining this niche should help answer why M. tuberculosis resists elimination from activated macrophages even in the face of T cell immunity.

ORGANISM(S): Mus musculus Mycobacterium tuberculosis

PROVIDER: GSE146127 | GEO | 2020/02/29

REPOSITORIES: GEO

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Project description:Tuberculosis, caused by M.tuberculosis (Mtb), remains an enduring global health challenge, especially given the limited efficacy of current therapeutic interventions. Much of existing research has focused on immune failure as a driver of tuberculosis. However, the crucial role of host macrophage biology in controlling the disease remains underexplored. While we have gained deeper insights into how alveolar macrophages (AMs) interact with Mtb, the precise AM subsets that mediate protection and potentially prevent tuberculosis progression have yet to be identified. In this study, by integrating the use of weighted gene correlation network analysis (WGCNA) modules with our multi-modal scRNA-seq protocol, we were able to evaluate the functional roles of diverse macrophage subpopulations across different infection timepoints, allowing us to delineate the dynamic landscape of controller and permissive AM populations throughout the infection timeline. Our analyses during specific post-Mtb challenge intervals revealed macrophage populations transitioning between distinct anti- and pro-inflammatory states. Notably, CD38- AMs showed a muted response to early Mtb infection. As infection progressed, we observed a phenotypic shift in AMs, with CD38+ monocyte-derived AMs (moAMs) and a subset of tissue-resident AMs (TR-AMs) emerging as significant controllers of bacterial growth. Interestingly, scATAC-seq analysis of naïve lungs demonstrated that CD38+ TR-AMs possessed a distinct chromatin signature prior to infection, indicative of epigenetic priming, and predisposed them to a pro-inflammatory response. BCG intranasal immunization increased the numbers of CD38+ macrophages, substantially enhancing their capability to restrict Mtb growth. Collectively, our findings emphasize the pivotal, dynamic roles of different macrophage subsets in TB infection and reveal rational pathways for the development of improved vaccines and immunotherapeutic strategies, with implications for the broader field of infectious diseases.

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CD11cHi monocyte-derived macrophages expressing CD38, CD14, and ABCA1 are the dominant niche for Mycobacterium tuberculosis

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