Pathogens, antibodies and graft fate: a translational perspective on pseudomonas aeruginosa in lung transplantation

Article review: Liao F, Zhou D, Cano M, Liu Z, Scozzi D, Tague LK, et al. Pseudomonas aeruginosa infection induces intragraft lymphocytotoxicity that triggers lung transplant antibody-mediated rejection. Sci Transl Med. 2025;17:eadp1349.

Antibody-mediated rejection (AMR) is increasingly recognized as a major cause of lung allograft failure and post-transplant mortality.1While infection surveillance and immunosuppression regimens form the core of post-transplant management, the contribution of specific pathogens to immunologic rejection has often been underappreciated. Pseudomonas aeruginosa is known as one of the most commonly isolated gram-negative bacteria in the early postoperative period2 and was previously found to demonstrate its independent association with the development of donor-specific antibodies (DSAs) and a significant increase in acute rejection grade ≥ A2 among the lung transplant recipients.3 The study published in Science Translational Medicine by Liao et al.4 compels surgeons and transplant teams to consider the unique and direct immunological consequences of P. aeruginosa infection in lung transplant recipients, paralleling ongoing efforts to bring basic science insights to clinical practice.

In their work4, retrospective human cohort analysis and mechanistic mouse models were leveraged to explore the association and mechanism between P. aeruginosa infection and AMR after lung transplantation. Specifically, they demonstrated that post-transplant patients with frequent positive cultures of P. aeruginosa, especially those who were pre-diagnosed as cystic fibrosis, had a 2- to 5-fold increased risk of developing AMR, independent of other variables. The experimental approach using a mouse lung transplant model further revealed that P. aeruginosa uses its Type III Secretion System (T3SS), notably the ExoT exotoxin out of four exotoxins,5 to induce apoptosis of Foxp3+CD4+ regulatory T cells within bronchus-associated lymphoid tissue in transplanted lungs. This loss of local immune control precipitates the expansion of T-bet+, CXCR3+ B cells, leading to the formation of highly avid, complement-fixing DSAs, driving rapid and severe AMR.6

The clinical relevance of this work is amplified by robust representation in both patient biopsies and murine models which shows AMR following P. aeruginosa infection depends on the formation of germinal center and memory B cells characterized by CXCR3 expression. Importantly, blockade or genetic knockout of CXCR3 in B cells was able to prevent AMR even in the presence of ongoing P. aeruginosa infection, offering promising avenues for future therapy. Indeed, P. aeruginosa has been shown to elevate CXC chemokines, in lung grafts including CXCL1, CXCL5 and IL-8 (CXCL8), that is associated with the development of bronchiolitis obliterans syndrome (BOS), which is a most common form of chronic allograft dysfunction limiting the patient survival, therefore, the revealed pathway could open a novel therapeutic option to improve posttransplant outcomes.7,8

However, certain limitations must be acknowledged. The patient cohort is dominated by cystic fibrosis cases, raising questions about generalizability to other diagnoses. The retrospective design may not capture all confounding variables, and mouse models cannot fully replicate the complexity of human immunobiology. Nonetheless, the link between bacterial virulence, acute lymphocytotoxicity, and immunologic graft rejection sets the stage for translational research and clinical innovation.