Cellular sources and targets of type I interferons that drive susceptibility to tuberculosis

Abstract

SummaryMycobacterium tuberculosis(Mtb) causes 1.5 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 interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN duringMtbinfection in mice and non-human primates, and pDCs localize near humanMtbgranulomas. Depletion of pDCs reducesMtbburdens, 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 reveals type I IFNs act on IMs to impair their responses to IFNγ, a cytokine critical forMtbcontrol. Cell type-specific disruption of the type I IFN receptor suggests IFNs act on IMs to inhibitMtbcontrol. We propose pDC-derived type I IFNs, driven by NETs, act on IMs to drive bacterial replication, further neutrophil recruitment, and active tuberculosis disease.