Mycobacterium tuberculosis infection drives a type I IFN signature in lung lymphocytes

Akter, Sharmin; Chauhan, Kuldeep S; Dunlap, Micah; Choreño-Parra, José Alberto; Lu, Lan; Esaulova, Ekaterina; Zúñiga, Joaquı́n; Artyomov, Maxim N.; Kaushal, Deepak; Khader, Shabaana A.

doi:10.1016/j.celrep.2022.110983

Cited by 22 publications

(31 citation statements)

References 70 publications

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“…Sp140 −/− mice provide a unique model of the aberrant type I IFN response, as they do not require repeated administration of TLR agonists, viral co-infection, or other perturbations of the innate immune system for type I IFN production 17,18,21,22,61 . Other groups have also modeled the type I IFN response by infecting B6 mice with a lineage 2 clinical Mtb strain, such as HN878 73,74 . However, IFNAR deletion had no impact on survival or bacterial control at early time points in B6 mice infected with HN878, unlike Sp140 −/− mice infected with Mtb Erdman 30,75,76 .…”

Section: Discussionmentioning

confidence: 99%

Early cellular mechanism of type I interferon-driven susceptibility to tuberculosis

Kotov¹,

Lee²,

Langner³

et al. 2022

Preprint

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Mycobacterium tuberculosis (Mtb) causes 1.5 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the underlying cellular mechanisms remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) known to activate pDCs. Single cell RNA-seq indicates that type I IFNs act on IMs to impair their responses to IFN gamma, a cytokine critical for Mtb control. Cell type-specific disruption of the type I IFN receptor suggests IFNs act on IMs to inhibit Mtb control. We propose pDC-derived type I IFNs, driven by NETs, act on IMs to drive bacterial replication, further neutrophil recruitment, and active tuberculosis disease.

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Section: Discussionmentioning

confidence: 99%

Early cellular mechanism of type I interferon-driven susceptibility to tuberculosis

Kotov¹,

Lee²,

Langner³

et al. 2022

Preprint

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“…Advances in single-cell RNA sequencing have provided unprecedented insights into the composition and function of immune cells in M.tb-infected tissues [34][35][36][37] .…”

Section: Discussionmentioning

confidence: 99%

Spatial mapping of human lung tissue reveals granuloma diversity and histopathological superstructure in tuberculosis

Sawyer

Patrick

Edwards

et al. 2022

Preprint

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SummaryThe histopathological hallmark of tuberculosis (TB) is the formation of immune cell enriched aggregates called granulomas, but the scope of granuloma heterogeneity in human TB is unknown. By spatially mapping individual immune cells across large regions of TB lung tissue, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages, indicating there are foci of distinct immune reactions adjacent to necrotizing granulomas. We further show that the specific cellular composition of non-necrotizing structures correlates with their proximity to necrotizing lesions. Together, our study shows that during tuberculosis diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.

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“…After eliminating intravascular cells, we identify naïve, proliferating, effector and exhausted CD8 T cells. CD8 T cells in cluster 8 had a signature of IFN-stimulated CD8 T cells, identified by the expression of IFN-regulated genes such as Ifit1, Bst2, Isg15, and Irf7, as has been described by Akter, Chauhan, et al for CD4 T cells 67 . Few genes associated with canonical effector function (i.e., Ifng, Prf1, etc.)…”

Section: Discussionmentioning

confidence: 59%

“…A spectrum of cellular states was detected including naïve (cluster 4), cycling (cluster 6), effector and polyfunctional (cluster 0, 7), and exhausted (cluster 1) CD8 T cells. CD8 T cells with a type I IFN signature (cluster 8) which expressed high levels of ISG15, IFIT1, IFIT2, and IRF7, were identified, like CD4 T cells from the lungs of HN878-infected mice 67 . GLIPH2 analysis identified the "RENS" motif as a dominant specificity group, which was restricted to CDR3β sequences of a similar length and shared V gene distribution as we had previously described for K b -restricted TB10.4 4-11 -specific CD8 T-cells with the "DRENSD" motif 26,27 .…”

Section: The Esx-1 Type VII Secretion System Is Required For Cross Pr...mentioning

confidence: 99%

High bacillary burden and the ESX-1 type VII secretion system promote MHC class I presentation byMycobacterium tuberculosisinfected macrophages to CD8 T-cells

Mott

Chang

Shinkawa

et al. 2022

Preprint

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Mycobacterium tuberculosis(Mtb) subverts host defenses to persist in macrophages despite immune pressure. CD4 T-cells can recognize macrophages infected with a single bacillusin vitro. Under identical conditions, CD8 T-cells inefficiently recognize infected macrophages and fail to restrict Mtb growth, although they can inhibit Mtb growth during high burden intracellular infection. We show that high intracellular Mtb numbers cause macrophage death, leading other macrophages to scavenge cellular debris and cross-present TB10.4 antigen to CD8 T-cells. Cross-presentation by heavily infected macrophages requires the ESX-1 type VII secretion system, indicating that phagosomal membrane damage and cell death promote class I MHC cross-presentation during Mtb infection. Single cell RNAseq shows TB10.4-specific CD8 T-cells are activated and resist T-cell exhaustion, particularly late during infection. Differences in the activation state between TB10.4-specific and other clonally expanded CD8 T-cells supports the idea that different microbial antigens can drive both beneficial and detrimental types of T-cell responses.

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Mycobacterium tuberculosis infection drives a type I IFN signature in lung lymphocytes

Cited by 22 publications

References 70 publications

Early cellular mechanism of type I interferon-driven susceptibility to tuberculosis

Early cellular mechanism of type I interferon-driven susceptibility to tuberculosis

Spatial mapping of human lung tissue reveals granuloma diversity and histopathological superstructure in tuberculosis

High bacillary burden and the ESX-1 type VII secretion system promote MHC class I presentation byMycobacterium tuberculosisinfected macrophages to CD8 T-cells

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