Mycoplasma fermentans infection induces human necrotic neuronal cell death via IFITM3-mediated amyloid-β (1-42)
Kyu-Young Sim1,2, Yeongseon Byeon2, So-Eun Bae1
1Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Abstract:
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.
Insights
Mycoplasma fermentans infects human brain cells, causing cell death via amyloid-beta deposition. Interferon-induced transmembrane protein 3 (IFITM3) plays a key role in this neuroinflammatory process.
Area of Science:
- Neuroscience
- Microbiology
- Infectious Diseases
Background:
- Mycoplasma fermentans is linked to neurological diseases and found in brain lesions.
- Its pathogenic role in human neuronal cells remains uninvestigated.
Purpose of the Study:
- To investigate the pathogenic mechanisms of Mycoplasma fermentans in human neuronal cells.
- To elucidate the role of M. fermentans in neuronal cell death and neurological disease progression.
Main Methods:
- Infection of human neuronal cells and brain organoids with M. fermentans.
- Amyloid-beta deposition analysis and amyloid precursor protein depletion using shRNA.
- RNA sequencing (RNA-seq) for differential gene expression analysis.
- Interferon-induced transmembrane protein 3 (IFITM3) knockdown and toll-like receptor 4 (TLR4) antagonist treatment.
Main Results:
- M. fermentans infects and replicates in human neuronal cells, inducing necrotic cell death.
- Necrotic cell death is associated with intracellular amyloid-beta (1-42) deposition.
- IFITM3 is upregulated upon M. fermentans infection and mediates amyloid-beta deposition and cell death.
- TLR4 signaling pathway is involved in IFITM3 upregulation.
- M. fermentans infection causes necrotic neuronal cell death in brain organoids.
Conclusions:
- Neuronal cell infection by M. fermentans directly induces necrotic cell death.
- This process is mediated by IFITM3-dependent amyloid-beta deposition.
- M. fermentans may contribute to neurological disease development and progression.
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