Pseudomonas aeruginosa Infection Induces Antibody-Mediated Rejection in Lung Transplantation

Academic Background Introduction

Lung transplantation is a critical treatment for end-stage lung diseases, but post-transplant rejection remains a major challenge affecting long-term patient survival. Antibody-mediated rejection (AMR) is an increasingly recognized form of lung transplant rejection that can lead to graft dysfunction and even death. Although the mechanisms underlying AMR are not fully understood, studies suggest that the production of donor-specific antibodies (DSAs) is closely associated with AMR. However, how pathogens influence transplant tolerance remains unclear.

Pseudomonas aeruginosa (P. aeruginosa) is a common bacterial pathogen in lung transplant recipients, particularly associated with pneumonia. Emerging evidence suggests a potential link between P. aeruginosa infection and AMR, but the specific mechanisms have not been systematically investigated. This study aimed to explore whether and how P. aeruginosa infection increases the risk of AMR in lung transplant recipients and to provide new strategies for its prevention and treatment.

Source and Authorship Information

This article was co-authored by Fuyi Liao, Dequan Zhou, Marlene Cano, and others. The research team primarily includes members from Washington University School of Medicine, University of Maryland School of Medicine, and the Medical College of Wisconsin. The paper was published in Science Translational Medicine on February 5, 2025, titled “Pseudomonas aeruginosa infection induces intragraft lymphocytotoxicity that triggers lung transplant antibody-mediated rejection.”

Research Process and Key Findings

1. Research Process

a) Human Retrospective Cohort Study

The research team first conducted a single-center retrospective cohort study, analyzing data from lung transplant recipients between January 1, 2008, and December 31, 2016. Follow-up data were collected until December 31, 2019, totaling 2816 patient-years. During the study period, 66 patients were diagnosed with AMR, including 23 definite AMR cases and 43 probable AMR cases. The results showed that P. aeruginosa infection was an independent risk factor for AMR, particularly in patients with cystic fibrosis (CF).

b) Mouse Lung Transplantation Model

To further investigate the relationship between P. aeruginosa infection and AMR, the research team established a mouse orthotopic lung transplantation model. C57BL/6 mice received lung transplants from BALB/c mice and were treated with anti-CD40L and CTLA4Ig to induce transplant tolerance. Thirty days post-transplantation, mice were intratracheally inoculated with the P. aeruginosa clinical isolate PA103. The study found that although PA103 was rapidly cleared from the graft and surrounding tissues, infected mice quickly developed high levels of IgM DSAs, which transitioned to IgG DSAs one month post-infection.

c) Bacterial Virulence Factor Study

The research team further explored the role of P. aeruginosa virulence factors in AMR. Using various PA103 mutant strains, they found that the type III secretion system (T3SS) was critical for inducing AMR. Specifically, the T3SS exotoxin ExoT promoted graft-resident Foxp3+CD4+ T cell apoptosis through its ADP ribosyltransferase (ADPRT) activity, thereby triggering AMR.

d) B Cell and CXCR3 Signaling Pathway Study

The study revealed that P. aeruginosa infection induced the differentiation of intragraft B cells, particularly the accumulation of CXCR3+ B cells. Using gene knockout mouse models, the researchers identified that the intrinsic MyD88 signaling pathway in B cells plays a crucial role in the generation of CXCR3+ B cells and the production of IgG2c DSAs. Additionally, CXCR3 deficiency or antibody blockade significantly suppressed AMR development.

2. Key Findings

a) P. aeruginosa Infection Increases AMR Risk

The retrospective cohort study demonstrated that P. aeruginosa infection is an independent risk factor for AMR in lung transplant recipients, with a particularly significant increase in AMR incidence among cystic fibrosis patients.

b) T3SS Exotoxin ExoT Induces Foxp3+CD4+ T Cell Apoptosis

Using the mouse model, the study found that graft-resident Foxp3+CD4+ T cells were significantly reduced within 18 hours of P. aeruginosa infection, with the ADPRT activity of the T3SS exotoxin ExoT being the key mechanism driving this apoptosis.

c) CXCR3+ B Cells Promote AMR Development

P. aeruginosa infection promoted the generation of intragraft CXCR3+ B cells, which exhibited high avidity for donor antigens and mediated IgG DSA production. Gene knockout and antibody blockade experiments demonstrated the critical role of the CXCR3 signaling pathway in AMR.

d) MyD88 Signaling Pathway Regulates B Cell Differentiation

The study also revealed that the intrinsic MyD88 signaling pathway in B cells drives AMR by promoting the differentiation of CXCR3+ B cells and the production of IgG2c DSAs.

Conclusion and Significance

This study is the first to reveal that P. aeruginosa infection induces AMR by triggering graft-resident Foxp3+CD4+ T cell apoptosis through the T3SS exotoxin ExoT. Additionally, the study elucidated the critical role of CXCR3+ B cells in AMR, providing important insights for developing new therapeutic strategies. Targeting T3SS or the CXCR3 signaling pathway may offer novel approaches to preventing and treating AMR in lung transplant recipients.

Research Highlights

1. First Link Between P. aeruginosa Infection and AMR: This study is the first to systematically elucidate the molecular mechanisms by which P. aeruginosa infection induces AMR through the T3SS exotoxin ExoT.
   
2. Key Role of T3SS Exotoxin ExoT: The ADPRT activity of ExoT was identified as the critical factor inducing Foxp3+CD4+ T cell apoptosis and AMR.
   
3. Role of CXCR3+ B Cells: The study highlighted the central role of CXCR3+ B cells in AMR, providing a basis for developing targeted therapies.
   
4. Discovery of B Cell MyD88 Signaling Pathway: This is the first study to identify the role of the intrinsic MyD88 signaling pathway in B cells in the differentiation of CXCR3+ B cells and AMR.

Additional Valuable Information

This study not only provides new perspectives on the mechanisms of AMR post-lung transplantation but also offers theoretical support for developing therapeutic strategies targeting T3SS or CXCR3. Future research into the roles of other P. aeruginosa virulence factors and their interactions with the immune system may further improve long-term outcomes for lung transplant recipients.