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

Abstract

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.

Immunosuppression is a conserved driver of tuberculosis susceptibility

“…Initially, we hypothesized that a likely candidate for a shared response to Mtb infection was type I IFN, as viral infections and the anti-viral type I IFN response correlate with the severity of Mtb disease in humans 2,65,[69][70][71] . A functional role for type I IFNs in driving Mtb disease is also observable in mice, as inducers of type I IFNs exacerbate Mtb infection in B6 mice 30,[72][73][74][75][76][77] whereas Ifnar1 deletion rescues bacterial control in Sst1 S and Sp140-deficient mice 16,17,28 . To our surprise, however, type I IFN receptor deletion had little to no effect on bacterial control in Nos2 -/and Acod1 -/mice (Fig.…”

“…We hypothesized that there may be conserved features underlying the susceptibility of diverse mouse models, and that these features may be preserved across susceptible mice, non-human primates, and humans. Neutrophilic inflammation is a major feature associated with tuberculosis disease across Sp140 -/-, Nos2 -/-, Acod1 -/and other susceptible mouse models 6,17,[19][20][21][22] , as well as during nonhuman primate 23,24 and human Mtb 3,25 . Depletion of neutrophils enhances bacterial control in diverse Mtb-susceptible mouse models, including Sp140 -/-, Nos2 -/-, and Acod1 -/mice 6,17,19 .…”

ATG5 suppresses type I IFN-dependent neutrophil swarming and NETosis

“…In particular, survival can be extended in mice that are hypersusceptible to M. tuberculosis infection due to elevated type I IFN signaling by inhibiting LTB4 synthesis with Zileuton and addition of PGE2 72 , supporting a link between type I IFN and LTB4 associated pathways, such as swarming. would also be expected to regulate neutrophil responses to type I IFN produced by other cell types during M. tuberculosis infection in vivo 12,40,74 . Indeed, NETs themselves can stimulate type I IFN production from plasmacytoid dendritic cells (pDCs) 38 and macrophages 73 , which may contribute to the heightened type I IFN signaling in ATG5-deficient neutrophils in vivo.…”

“…The increased type I IFN signaling detected in lung neutrophils during M. tuberculosis infection of Atg5 fl/fl -LysM-Cre mice implies that there is a positive feedback loop occurring that induces increased type I IFN production in the absence of ATG5 in vivo . The neutrophil-intrinsic role for ATG5 would also be expected to regulate neutrophil responses to type I IFN produced by other cell types during M. tuberculosis infection in vivo 12,40,74 . Indeed, NETs themselves can stimulate type I IFN production from plasmacytoid dendritic cells (pDCs) 38 and macrophages 73 , which may contribute to the heightened type I IFN signaling in ATG5-deficient neutrophils in vivo .…”

“…4L), further supporting that ATG5 suppresses type I IFN-induced neutrophil swarming during M. tuberculosis infection in vivo. would also be expected to regulate neutrophil responses to type I IFN produced by other cell types during M. tuberculosis infection in vivo 12,40,74 . Indeed, NETs themselves can stimulate type I IFN production from plasmacytoid dendritic cells (pDCs) 38 and macrophages 73 , which may contribute to the heightened type I IFN signaling in ATG5-deficient neutrophils in vivo.…”