Transient Staphylococcus aureus Infection Promotes Sustained Intervertebral Disc Degeneration Through the ATF-3/CHOP Pathway.

Abstract

Background: Infection with Staphylococcus aureus (S. aureus) is an important contributor to intervertebral disc degeneration (IDD). Endoplasmic reticulum stress (ERS) is a major pathway through which bacteria regulate cell fate. The aim of this study was to examine the role of ERS in S. aureus-induced IDD.

Methods: We assessed the S. aureus-induced degeneration, apoptosis, and senescence of nucleus pulposus cells (NPCs) in vitro by Western blot, flow cytometry, and staining for β-galactosidase, and in vivo by magnetic resonance imaging/computed tomography (MRI/CT) imaging, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and histological staining. RNA sequencing was conducted to identify differentially expressed genes, while siRNA, lentiviral vectors, and Atf3-knockout (Atf3-KO) mice were utilized to confirm the role of ATF3 in persistent IDD following transient S. aureus infection.

Results: Following the eradication of S. aureus in vitro, the expression of Aggrecan and collagen II in NPCs continued to decline, accompanied by an increase in the proportion of apoptotic and senescent cells. Transient S. aureus infection was shown to activate the Activating Transcription Factor 3 (ATF3)-CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) signaling pathway, leading to sustained swelling of the endoplasmic reticulum in NPCs. In vivo experiments further demonstrated that transient S. aureus infection resulted in progressive IDD, activation of the ATF3-CHOP pathway, increased numbers of TUNEL-positive cells, and elevated P21 expression. Knockdown of ATF3 expression in vitro attenuated the S. aureus-mediated increase in apoptotic and senescent cells, while Atf3-KO mice exhibited milder IDD compared to wild type (WT) mice, with fewer apoptotic cells and reduced P21 expression.

Conclusion: Transient S. aureus infection may lead to progressive IDD by triggering sustained ER stress and activating related signaling pathways. The ATF3-CHOP pathway may be an important target for alleviating the sustained disc degeneration caused by transient S. aureus infection.