Linking highly neutralizing human antibodies targeting multidrug-resistant Pseudomonas aeruginosa to clinical and immunological phenotype in people with cystic fibrosis

Multidrug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for novel therapeutic approaches. In people with cystic fibrosis (pwCF), PA frequently establishes chronic infections in the lung. We previously demonstrated that repeated exposure to PA can elicit highly neutralizing antibodies directed against its type III secretion system (T3SS). However, the immunological dynamics underlying chronic infection and the clinical significance of these antibodies remain poorly understood. To address this, we integrated clinical data and serum T3SS-neutralizing activity from 99 pwCF and 12 healthy individuals with immunophenotyping of immune cell populations and bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs). As expected, prolonged PA infection was associated with reduced lung function. Although chronic infection correlated with the presence of high titers of T3SS-neutralization antibodies (PA-Ab high ), these antibodies did not confer measurable protection against lung function decline, consistent with previous findings that the T3SS plays a subordinate role in chronic lung infections. Importantly, comparison of pwCF with high versus low neutralization capacity revealed distinct immune signatures: Flow cytometry demonstrated altered CD8+ T-cell profiles in PA-Ab high individuals, marked by expansion of terminal effector subsets and reduction of naïve CD8+ T cells. These cellular alterations were mirrored in transcriptomic differences, particularly within cytokine–cytokine receptor interaction and adaptive immunity pathways. In conclusion, our findings provide mechanistic insight into the development of highly neutralizing anti-T3SS antibodies and identify a distinct immunological profile associated with chronic PA infection and impaired lung function. Incorporating this immune signature into clinical practice may support the early identification of patients at risk of disease progression. Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany