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

Dmitri I. Kotov; Ophelia V. Lee; Stefan A. Fattinger; Charlotte A. Langner; Jaresley V. Guillen; Joshua M. Peters; Andres Moon; Eileen M. Burd; Kristen C. Witt; Daniel B. Stetson; David L. Jaye; Bryan D. Bryson; Russell E. Vance

doi:10.1016/j.cell.2023.11.002

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

Dmitri I. Kotov, Ophelia V. Lee, Stefan A. Fattinger, Charlotte A. Langner, Jaresley V. Guillen, Joshua M. Peters, Andres Moon, Eileen M. Burd, Kristen C. Witt, Daniel B. Stetson, David L. Jaye, Bryan D. Bryson, Russell E. Vance

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis 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) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.

Original language	English
Pages (from-to)	5536-5553.e22
Journal	Cell
Volume	186
Issue number	25
DOIs	https://doi.org/10.1016/j.cell.2023.11.002
State	Published - Dec 7 2023

Keywords

innate immunology
interstitial macrophages
lung
mice
Mycobacterium tuberculosis
neutrophil extracellular traps
neutrophils
plasmacytoid dendritic cells
type I interferons

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10.1016/j.cell.2023.11.002

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@article{9ac1868c2e864704a37de03b53d14579,

title = "Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis",

abstract = "Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis 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) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.",

keywords = "innate immunology, interstitial macrophages, lung, mice, Mycobacterium tuberculosis, neutrophil extracellular traps, neutrophils, plasmacytoid dendritic cells, type I interferons",

author = "Kotov, {Dmitri I.} and Lee, {Ophelia V.} and Fattinger, {Stefan A.} and Langner, {Charlotte A.} and Guillen, {Jaresley V.} and Peters, {Joshua M.} and Andres Moon and Burd, {Eileen M.} and Witt, {Kristen C.} and Stetson, {Daniel B.} and Jaye, {David L.} and Bryson, {Bryan D.} and Vance, {Russell E.}",

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year = "2023",

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doi = "10.1016/j.cell.2023.11.002",

language = "English",

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T1 - Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis

AU - Kotov, Dmitri I.

AU - Lee, Ophelia V.

AU - Fattinger, Stefan A.

AU - Langner, Charlotte A.

AU - Guillen, Jaresley V.

AU - Peters, Joshua M.

AU - Moon, Andres

AU - Burd, Eileen M.

AU - Witt, Kristen C.

AU - Stetson, Daniel B.

AU - Jaye, David L.

AU - Bryson, Bryan D.

AU - Vance, Russell E.

PY - 2023/12/7

Y1 - 2023/12/7

N2 - Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis 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) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.

AB - Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis 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) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.

KW - innate immunology

KW - interstitial macrophages

KW - lung

KW - mice

KW - Mycobacterium tuberculosis

KW - neutrophil extracellular traps

KW - neutrophils

KW - plasmacytoid dendritic cells

KW - type I interferons

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DO - 10.1016/j.cell.2023.11.002

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AN - SCOPUS:85178092505

SN - 0092-8674

VL - 186

SP - 5536-5553.e22

JO - Cell

JF - Cell

IS - 25

ER -

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

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