Borbora Salik Miskat, Satish Bijewar Ashish, Sundar Smriti, B Mahima, Bhatt Sneha, Balaji Kithiganahalli Narayanaswamy
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India.
J Infect Dis. 2023 May 9. doi: 10.1093/infdis/jiad126.
During infection, Mycobacterium tuberculosis (Mtb) rewires distinct host signaling pathways that results in pathogen-favorable outcomes. Oxidative stress build-up is a key cellular manifestation that occurs due to the cumulative effect of elevated reactive oxygen species generation (ROS) and the inept ability of the cell to mitigate ROS levels. Here, we report the Mtb-induced expression of the neuronal ligand, SLIT2, to be instrumental in ROS accumulation during infection. Loss of function analysis revealed the heightened expression of SLIT2 to be dependent on the Mtb-mediated phosphorylation of the P38/JNK pathways. Activation of these kinases resulted in the loss of the repressive H3K27me3 signature on the Slit2 promoter. Furthermore, SLIT2 promoted the expression of Vanin1 (VNN1), that contributed to copious levels of ROS within the host. Thus, we dissect the pathway leading to the robust expression of SLIT2 during Mtb infection while outlining the potential consequences of SLIT2 upregulation in infected macrophages.
在感染过程中，结核分枝杆菌（Mtb）重塑不同的宿主信号通路，从而产生有利于病原体的结果。氧化应激积累是一种关键的细胞表现，它是由于活性氧生成（ROS）增加的累积效应以及细胞减轻ROS水平的能力不足而发生的。在这里，我们报告Mtb诱导的神经元配体SLIT2的表达在感染期间的ROS积累中起重要作用。功能丧失分析表明，SLIT2的高表达依赖于Mtb介导的P38/JNK通路的磷酸化。这些激酶的激活导致Slit2启动子上抑制性H3K27me3标记的丧失。此外，SLIT2促进了Vanin1（VNN1）的表达，这导致宿主体内大量的ROS。因此，我们剖析了Mtb感染期间导致SLIT2强烈表达的途径，同时概述了SLIT2上调在感染巨噬细胞中的潜在后果。
