| First Author | Kotov DI | Year | 2023 |
| Journal | Cell | Volume | 186 |
| Issue | 25 | Pages | 5536-5553.e22 |
| PubMed ID | 38029747 | Mgi Jnum | J:343796 |
| Mgi Id | MGI:7564349 | Doi | 10.1016/j.cell.2023.11.002 |
| Citation | Kotov DI, et al. (2023) Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis. Cell |
| abstractText | 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 IFNgamma, 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. |
