Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
Sci Rep. 2023 Apr 26;13(1):6864. doi: 10.1038/s41598-023-34105-y.
Mycoplasma fermentans is a proposed risk factor of several neurological diseases that has been detected in necrotic brain lesions of acquired immunodeficiency syndrome patients, implying brain invasiveness. However, the pathogenic roles of M. fermentans in neuronal cells have not been investigated. In this study, we found that M. fermentans can infect and replicate in human neuronal cells, inducing necrotic cell death. Necrotic neuronal cell death was accompanied by intracellular amyloid-β (1-42) deposition, and targeted depletion of amyloid precursor protein by a short hairpin RNA (shRNA) abolished necrotic neuronal cell death. Differential gene expression analysis by RNA sequencing (RNA-seq) showed that interferon-induced transmembrane protein 3 (IFITM3) was dramatically upregulated by M. fermentans infection, and knockdown of IFITM3 abolished both amyloid-β (1-42) deposition and necrotic cell death. A toll-like receptor 4 antagonist inhibited M. fermentans infection-mediated IFITM3 upregulation. M. fermentans infection also induced necrotic neuronal cell death in the brain organoid. Thus, neuronal cell infection by M. fermentans directly induces necrotic cell death through IFITM3-mediated amyloid-β deposition. Our results suggest that M. fermentans is involved in neurological disease development and progression through necrotic neuronal cell death.
发酵支原体是几种神经疾病的潜在风险因素，已在获得性免疫缺陷综合征患者的坏死性脑损伤中检测到，表明其具有侵袭脑组织的能力。然而，发酵支原体在神经元细胞中的致病作用尚未得到研究。在本研究中，我们发现发酵支原体可以感染并在人神经元细胞中复制，诱导坏死性细胞死亡。坏死性神经元细胞死亡伴随着细胞内淀粉样β（1-42）沉积，通过短发夹 RNA（shRNA）靶向敲低淀粉样前体蛋白可消除坏死性神经元细胞死亡。通过 RNA 测序（RNA-seq）进行的差异基因表达分析表明，发酵支原体感染显著上调了干扰素诱导的跨膜蛋白 3（IFITM3），IFITM3 的敲低消除了淀粉样β（1-42）沉积和坏死性细胞死亡。Toll 样受体 4 拮抗剂抑制了发酵支原体感染介导的 IFITM3 上调。发酵支原体感染也诱导了脑类器官中的坏死性神经元细胞死亡。因此，发酵支原体对神经元细胞的感染通过 IFITM3 介导的淀粉样β沉积直接诱导坏死性细胞死亡。我们的研究结果表明，发酵支原体通过坏死性神经元细胞死亡参与了神经疾病的发生和发展。
