Activation of NF-κB/MAPK signaling and induction of apoptosis by salicylate synthase NbtS in Nocardia farcinica promotes neuroinflammation development

作者：Jirao Shen, Xing zhao Ji, Lichao Han, Jiang Yao, Yihe Liang, Min Yuan, Shuai Xu, Zhenjun Li · 发表于：mSystems · 年份：2024 · DOI：10.1128/msystems.00893-24 · 被引用次数：10 · 研究领域：Actinomycetales infections and treatment、Mycobacterium research and diagnosis、Burkholderia infections and melioidosis

ABSTRACT Nocardia farcinica can cause a rare, yet potentially fatal, central nervous system infection. NbtS protein may be a key virulence factor in N. farcinica infection of the brain. In this study, we investigated the function of the virulence-associated factor NbtS in microglial cells in vitro and in infected mice in vivo . We explored the interactions between NbtS and microglial cells (BV2 and human microglial clone 3), revealing that NbtS activates the toll-like receptor 4-dependent MyD88-IRAK4-IRAK1 and MAPK/nuclear factor kappa B (NF-κB) pathways, significantly enhancing pro-inflammatory responses as indicated by increased levels of tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), as measured by ELISA and quantitative PCR. Apoptosis was elevated in these cells, as shown by increased expression of Bax and caspase-3 and decreased Bcl-2 levels. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay also confirmed the occurrence of apoptosis. In vivo, mice infected with an RS03155 -deficient strain of N. farcinica exhibited higher survival rates and reduced brain inflammation, suggesting a pivotal role for the NbtS protein in the pathogenesis of Nocardia . Conservation of the RS03155 gene across Nocardia spp. was verified by PCR, and the immunogenic potential of NbtS was confirmed by Western blot analysis using sera from infected mice. These findings suggest that targeting NbtS may offer a novel therapeutic strategy against Nocardia infectio...