Proteomic and bioinformatic profiling of neutrophils in CLL reveals functional defects that predispose to bacterial infections

Author:

Subramaniam Nirojah12ORCID,Bottek Jenny1ORCID,Thiebes Stephanie1ORCID,Zec Kristina13ORCID,Kudla Matthias1ORCID,Soun Camille1ORCID,de Dios Panal Elena14ORCID,Lill Julia K.15,Pfennig Aaron6ORCID,Herrmann Ralf7,Bruderek Kirsten8,Rahmann Sven6ORCID,Brandau Sven8,Johansson Patricia9ORCID,Reinhardt Hans Christian9,Dürig Jan9,Seiffert Martina10,Bracht Thilo1112ORCID,Sitek Barbara11,Engel Daniel Robert1ORCID

Affiliation:

1. Institute of Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, Essen, Germany;

2. Bayer AG, Pharma Research Center, Wuppertal, Germany;

3. Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom;

4. University Medical Centre Utrecht, Center for Translational Immunology, Utrecht, The Netherlands;

5. Leibniz-Institut für Analytische Wissenschaften, Leibniz-Institut für Analytische Wissenschaften (ISAS–e.V.), Dortmund, Germany;

6. Genome Informatics, Institute of Human Genetics,

7. Division of Neonatology, Kinderklinik I, University Hospital Essen, University Duisburg-Essen, Essen, Germany;

8. Research Division, Department of Otorhinolaryngology, University Hospital Essen, West German Cancer Center, Essen, Germany;

9. Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Consortium for Translational Cancer Research, University Hospital Essen, University Duisburg-Essen, Essen, Germany;

10. Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;

11. Medizinisches Proteom-Center, Medical Faculty, Ruhr-University Bochum, Bochum, Germany; and

12. Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Germany

Abstract

Abstract Patients with chronic lymphocytic leukemia (CLL) typically suffer from frequent and severe bacterial infections. Although it is well known that neutrophils are critical innate immune cells facilitating the early defense, the underlying phenotypical and functional changes in neutrophils during CLL remain largely elusive. Using a murine adoptive transfer model of CLL, we demonstrate aggravated bacterial burden in CLL-bearing mice upon a urinary tract infection with uropathogenic Escherichia coli. Bioinformatic analyses of the neutrophil proteome revealed increased expression of proteins associated with interferon signaling and decreased protein expression associated with granule composition and neutrophil migration. Functional experiments validated these findings by showing reduced levels of myeloperoxidase and acidification of neutrophil granules after ex vivo phagocytosis of bacteria. Pathway enrichment analysis indicated decreased expression of molecules critical for neutrophil recruitment, and migration of neutrophils into the infected urinary bladder was significantly reduced. These altered migratory properties of neutrophils were also associated with reduced expression of CD62L and CXCR4 and correlated with an increased incidence of infections in patients with CLL. In conclusion, this study describes a molecular signature of neutrophils through proteomic, bioinformatic, and functional analyses that are linked to a reduced migratory ability, potentially leading to increased bacterial infections in patients with CLL.

Publisher

American Society of Hematology

Subject

Hematology

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