小柯机器人

美国加州大学伯克利分校Russell E. Vance等研究人员合作阐明I型干扰素驱动结核病易感性的早期细胞机制。相关论文于2023年11月28日在线发表于国际学术期刊《细胞》。

研究人员发现，在小鼠和非人灵长类动物感染Mtb期间，间质巨噬细胞（IM）和浆细胞状树突状细胞（pDC）是I型干扰素的主要产生者，而pDC定位于人类结核分枝杆菌（Mtb）肉芽肿附近。耗竭pDC可减少Mtb负担，这表明pDC与结核病的发病机制有关。在IFN驱动的疾病期间，研究人员观察到大量含有DNA的中性粒细胞胞外捕获物（NET），这些捕获物被描述为能激活pDC。

I型IFN受体的细胞特异性破坏表明，IFN作用于IM以抑制Mtb的控制。单细胞RNA测序（scRNA-seq）表明，I型IFN反应细胞对IFNγ的反应存在缺陷，而IFNγ是一种对Mtb控制至关重要的细胞因子。研究人员认为，pDC衍生的I型IFN作用于IM，允许细菌复制，从而推动了中性粒细胞的进一步招募和活动性结核病的发生。

据介绍，Mtb每年导致160万人死亡。活动性结核病与中性粒细胞驱动的I型干扰素（IFN）特征相关，但人们对结核病发病的细胞机制仍然知之甚少。

附：英文原文

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

Author: 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

Issue&Volume: 2023-11-28

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.

DOI: 10.1016/j.cell.2023.11.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01217-5