CD11cHi monocyte-derived macrophages are a major cellular compartment infected by Mycobacterium tuberculosis

Lee, Jin‐Hee; Boyce, Shayla; Powers, Jennifer; Baer, Christina E.; Sassetti, Christopher M.; Behar, Samuel M.

doi:10.1371/journal.ppat.1008621

Cited by 57 publications

(125 citation statements)

References 68 publications

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“…Consistent with this observation, we found that expression of CD11c correlated inversely with both bacterial stress (hspx9::GFP) and drug tolerance, which indicates that CD11c + IMs are permissive for Mtb growth. The identification of a CD11c + , Mtb-infected IM population both in our study and that of Lee et al (2020) raises the possibility that recruited, monocyte-derived macrophages can also give rise to a subpopulation of permissive host phagocytes capable of supporting bacterial expansion and disease progression.…”

Section: Discussionsupporting

confidence: 52%

“…To date, CD11c and SiglecF have been used as ontogenic markers to separate AMs from IMs. Recently, this notion has been challenged by the identification of a population of Mtb-infected monocyte-derived macrophages that are CD11c high (Lee et al, 2020). Using ADT staining, we reclustered the infected cells based on the expression of surface markers rather than transcriptional profile.…”

Section: Expression Of the Surface Marker Cd11c Is Inversely Associated With Drug-tolerant Bacteriamentioning

confidence: 99%

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Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Pisu

Huang

Narang

et al. 2021

Journal of Experimental Medicine

107

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In this study, we detail a novel approach that combines bacterial fitness fluorescent reporter strains with scRNA-seq to simultaneously acquire the host transcriptome, surface marker expression, and bacterial phenotype for each infected cell. This approach facilitates the dissection of the functional heterogeneity of M. tuberculosis–infected alveolar (AMs) and interstitial macrophages (IMs) in vivo. We identify clusters of pro-inflammatory AMs associated with stressed bacteria, in addition to three different populations of IMs with heterogeneous bacterial phenotypes. Finally, we show that the main macrophage populations in the lung are epigenetically constrained in their response to infection, while inter-species comparison reveals that most AMs subsets are conserved between mice and humans. This conceptual approach is readily transferable to other infectious disease agents with the potential for an increased understanding of the roles that different host cell populations play during the course of an infection.

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Section: Discussionsupporting

confidence: 52%

Section: Expression Of the Surface Marker Cd11c Is Inversely Associated With Drug-tolerant Bacteriamentioning

confidence: 99%

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Pisu

Huang

Narang

et al. 2021

Journal of Experimental Medicine

107

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“…In separate studies with 8 mice per treatment group from 3 independent studies and following mouse euthanasia and lung perfusion, lungs were inflated with 1 ml digestion solution/mouse containing 0.5 mg/ml Liberase TM [17][18][19][20].…”

Section: Lung Cell Sortingmentioning

confidence: 99%

High-throughput analysis of lung immune cells in a combined murine model of agriculture dust-triggered airway inflammation with rheumatoid arthritis

et al. 2021

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Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.

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“…The distinct capabilities of these populations in controlling Mtb growth have emerged recently in studies using a mouse model (Huang et al 2018). Resident alveolar macrophages present a permissive environment for Mtb growth (Huang et al 2018) and decrease in numbers during the course of infection (Lee et al 2020). Whereas, interstitial macrophages, derived from blood monocytes, accumulate in lungs, exhibit a Th1-like celltype and restrict bacterial growth (Huang et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Variations in human monocyte-derived macrophage antimicrobial activities and their associations with tuberculosis clinical manifestations

Tram

Thu

et al. 2020

Preprint

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Macrophages play a significant role in preventing infection through antimicrobial activities, particularly acidification and proteolysis. Mycobacterium tuberculosis infection can lead to diverse outcomes, from latent asymptomatic infection to active disease involving multiple organs. Monocyte-derived macrophage is one of the main cell types accumulating in lungs following Mtb infection. The variation of intracellular activities of monocyte-derived macrophages in humans and the influence of these activities on the tuberculosis (TB) spectrum are not well understood. By exploiting ligand-specific bead-based assays, we investigated macrophage antimicrobial activities real-time in healthy volunteers (n=53) with 35 cases of latent TB (LTB), and those with active TB (ATB) and either pulmonary TB (PTB, n=70) or TB meningitis (TBM, n=77). We found wide person-to-person variations in acidification and proteolytic activities in response to both non-immunogenic IgG and pathogenic ligands comprising trehalose 6,6'-dimycolate (TDM) from Mycobacterium tuberculosis or beta-glucan from Saccharamyces cerevisiase. The variation in the macrophage activities remained similar regardless of stimuli; however, IgG induced stronger acidification activity than immunogenic ligands TDM (P=10e-5, 3x10e-5 and 0.01 at 30, 60 and 90 min) and beta-glucan (P=10e-4, 3x10e-4 and 0.04 at 30, 60 and 90 min). Variation in proteolysis activity was slightly higher in LTB than in ATB (CV=40% in LTB vs. 29% in ATB, P= 0.03). There was no difference in measured antimicrobial activities in response to TDM and bacterial killing in macrophages from LTB and ATB, or from PTB and TBM. Our results indicate that antimicrobial activities of monocyte-derived macrophages vary among individuals and show immunological dependence, but suggest these activities cannot be solely responsible for the control of bacterial replication or dissemination in TB.

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CD11cHi monocyte-derived macrophages are a major cellular compartment infected by Mycobacterium tuberculosis

Cited by 57 publications

References 68 publications

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung

High-throughput analysis of lung immune cells in a combined murine model of agriculture dust-triggered airway inflammation with rheumatoid arthritis

Variations in human monocyte-derived macrophage antimicrobial activities and their associations with tuberculosis clinical manifestations

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