Department of Bioengineering, Stanford, CA, USA; Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA.
Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford, CA, USA.
Cell Syst. 2019 Mar 27;8(3):183-196.e4. doi: 10.1016/j.cels.2019.02.008. Epub 2019 Mar 20.
During an infection, immune cells must identify the specific level of threat posed by a given bacterial input in order to generate an appropriate response. Given that they use a general non-self-recognition system, known as Toll-like receptors (TLRs), to detect bacteria, it remains unclear how they transmit information about a particular threat. To determine whether host cells can use signaling dynamics to transmit contextual information about a bacterial stimulus, we use live-cell imaging to make simultaneous quantitative measurements of host MAPK and NF-κB signaling, two key pathways downstream of TLRs, and bacterial infection and load. This combined, single-cell approach reveals that NF-κB and MAPK signaling dynamics are sufficient to discriminate between (1) pathogen-associated molecular patterns (PAMPs) versus bacteria, (2) extracellular versus intracellular bacteria, (3) pathogenic versus non-pathogenic bacteria, and (4) the presence or absence of features indicating an active intracellular bacterial infection, such as replication and effector secretion.
在感染过程中，免疫细胞必须识别特定细菌输入所带来的威胁程度，以便产生适当的反应。鉴于它们使用一种通用的非自身识别系统，即 Toll 样受体 (TLR) 来检测细菌，目前尚不清楚它们如何传递有关特定威胁的信息。为了确定宿主细胞是否可以利用信号转导动力学来传递有关细菌刺激的上下文信息，我们使用活细胞成像技术同时对 MAPK 和 NF-κB 信号进行定量测量，这两种信号通路是 TLR 下游的两个关键途径，以及细菌感染和负荷。这种组合的单细胞方法表明，NF-κB 和 MAPK 信号转导动力学足以区分 (1) 病原体相关分子模式 (PAMP) 与细菌，(2) 细胞外与细胞内细菌，(3) 致病性与非致病性细菌，以及 (4) 指示细胞内细菌感染活性的特征的存在或不存在，例如复制和效应物分泌。
