Epstein–Barr Virus Infection Exacerbates Ulcerative Colitis by Driving Macrophage Pyroptosis via the Upregulation of Glycolysis

Infectious Diseases Life Sciences Gastroenterology Medicine Immunology
Epstein-Barr virus ulcerative colitis macrophages pyroptosis glycolysis

Academic Background

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent inflammation and ulceration of the colonic mucosa. Current treatments for UC primarily rely on immunosuppressive drugs, such as corticosteroids, immunomodulators, and biologics. However, the immunosuppressive properties of these drugs increase the risk of opportunistic infections, including Epstein-Barr Virus (EBV). Previous studies have shown that EBV infection is associated with clinical symptoms, treatment response, the need for surgical intervention, and an increased risk of lymphoma in UC patients. However, existing research has mainly focused on the epidemiological and clinical associations between EBV and UC, while the mechanisms by which EBV exacerbates colitis remain unclear.

Macrophages play a crucial role in the pathogenesis of UC, and pyroptosis, a form of programmed cell death regulated by inflammasomes, is closely related to the amplification of inflammatory responses. Glycolysis, as a core pathway of energy metabolism, not only plays a key role in energy production but also regulates immune cell function. Recent studies have found that glycolysis is significantly upregulated in inflammatory diseases and may exacerbate inflammatory responses by activating macrophage pyroptosis. However, whether EBV infection drives macrophage pyroptosis through glycolysis, thereby exacerbating UC inflammation, remains an unanswered question.

Source of the Paper

This paper was co-authored by Chunxiang Ma, Kexin Chen, Lili Li, and others, from the Department of Gastroenterology, West China Hospital of Sichuan University, the Center for Inflammatory Bowel Disease, and the Frontiers Science Center for Disease-Related Molecular Network. The paper was published on January 21, 2025, in the journal Precision Clinical Medicine, titled “Epstein–Barr Virus Infection Exacerbates Ulcerative Colitis by Driving Macrophage Pyroptosis via the Upregulation of Glycolysis.”

Research Process and Results

1. Clinical Sample Analysis and Correlation with EBV Infection

The study first collected colonic mucosal samples from UC patients and detected EBV infection using EBV-encoded RNA (EBER) in situ hybridization (EBER-ISH). The results showed that the expression of pyroptosis markers (IL-18, IL-1β, GSDMD) in the colonic tissues of EBV-positive UC patients was significantly higher than in EBV-negative patients. Additionally, Pearson correlation analysis revealed that the expression of macrophage pyroptosis markers was positively correlated with clinical disease activity indicators (such as platelet count and C-reactive protein) in UC patients. These results indicate that EBV infection is closely associated with the activation of macrophage pyroptosis in UC patients, and this activation is related to disease severity.

2. Mouse Model Validation of EBV Infection’s Impact on Colitis

To further validate the impact of EBV infection on colitis, the research team used murine gammaherpesvirus 68 (MHV-68) to simulate EBV infection and combined it with a dextran sulfate sodium (DSS)-induced colitis model. The results showed that MHV-68 infection significantly exacerbated DSS-induced colitis, manifested by increased inflammatory cell infiltration and mucosal damage in the colonic tissues. Moreover, MHV-68 infection upregulated the expression of pyroptosis-related molecules (NLRP3, IL-1β, GSDMD, IL-18) in colonic tissues and peritoneal macrophages. These findings further support the hypothesis that EBV infection exacerbates colitis by activating macrophage pyroptosis.

3. In Vitro Experiments Validate EBV’s Direct Role in Macrophage Pyroptosis

The research team conducted in vitro experiments using human monocytic leukemia cells (THP-1) and mouse bone marrow-derived macrophages (BMDMs), stimulating them with EBV and MHV-68, respectively. The results showed that both EBV and MHV-68 directly induced macrophage pyroptosis, as evidenced by the upregulation of pyroptosis-related molecules (NLRP3, IL-1β, GSDMD, IL-18). Additionally, EBV and MHV-68 promoted the secretion of pro-inflammatory cytokines (TNF-α, IL-6) in macrophages while suppressing the expression of the anti-inflammatory cytokine IL-10. These results indicate that EBV infection amplifies inflammatory responses by directly activating macrophage pyroptosis.

4. The Role of Glycolysis in EBV-Induced Macrophage Pyroptosis

To explore the role of glycolysis in EBV-induced macrophage pyroptosis, the research team examined the expression of glycolysis-related genes (GLUT1, PFKFB3, HIF, etc.) in peritoneal macrophages of MHV-68-infected mice. The results showed that MHV-68 infection significantly upregulated the expression of glycolysis-related genes. Furthermore, in vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) could inhibit MHV-68-induced macrophage pyroptosis. These findings reveal the critical role of glycolysis in EBV-induced macrophage pyroptosis.

Research Conclusions and Significance

This study demonstrates that EBV infection exacerbates UC inflammation by upregulating glycolysis to drive macrophage pyroptosis. This discovery not only reveals a new mechanism of EBV infection in the pathogenesis of UC but also provides a potential new target for UC treatment. Inhibiting glycolysis or macrophage pyroptosis may help alleviate EBV-related intestinal inflammation.

Research Highlights

  1. Mechanistic Innovation: For the first time, the study reveals the mechanism by which EBV infection exacerbates UC inflammation through glycolysis-driven macrophage pyroptosis.
  2. Model Innovation: The use of MHV-68 to simulate EBV infection provides a reliable animal model for studying the role of EBV in UC.
  3. Therapeutic Potential: The study finds that glycolysis inhibitors can suppress EBV-induced macrophage pyroptosis, offering new insights for UC treatment.

Other Valuable Information

The research team also noted that future studies should further explore the impact of EBV infection on other immune cells (such as neutrophils and lymphocytes) to comprehensively understand EBV’s role in the pathogenesis of UC. Additionally, validation using primary human macrophages (e.g., CD14+ cells) will help further confirm EBV’s role in inducing macrophage pyroptosis.

Through this research, we have deepened our understanding of the role of EBV infection in UC and provided a scientific basis for developing new treatment strategies. This achievement lays an important foundation for future clinical research and therapeutic practice.