Suppression of the innate anti-bacterial response in Chronic Lymphocytic Leukemia

• Applicants: Professor Dr. Daniel Robert Engel; Professorin Dr. Barbara Sitek
• Subject Area: Immunology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314635618

• Final Report Year: 2020

Final Report Abstract

Patients with chronic lymphocytic leukemia (CLL) 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 are elusive. Using the murine adoptive transfer model of CLL, we demonstrate aggravated bacterial burden in CLL- bearing mice upon a urinary tract infection of the urinary bladder with uropathogenic E.coli. Bioinformatic analyses of the neutrophil proteome revealed not only increased signatures of interferon-signaling, but also 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 migration, and neutrophil migration in vivo into the infected urinary bladder was insufficient. The changed migration properties of neutrophils was also evident in the reduced expression of CD62L and CXCR4 in CLL-bearing mice and also treatment-naïve CLL patients showed a similar neutrophil phenotype (CD62Llow CXCR4low). In conclusion, this study describes through proteomic and functional analyzes a molecular signature of neutrophils, which is linked to a reduced and migratory ability, potentially leading to increased bacterial infections in CLL patients.

Publications

• Neutrophil Migration into the Infected Uroepithelium Is Regulated by the Crosstalk between Resident and Helper Macrophages. Pathogens, 5. (2016)
  Zec K, Volke J, Vijitha N, Thiebes S, Gunzer M, Kurts C, Engel, DR
  
• Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus. Gut, 12, 2110-2120 (2017)
  Pohl JM, Gutweiler S, Thiebes S, Volke J, Klein-Hitpass L, Zwanziger D, Gunzer M, Jung S, Agace W, Kurts C, Engel DR
  
• CCR2-dependent Gr1high monocytes promote kidney injury in shiga toxininduced hemolytic uremic syndrome in mice. Eur J Immunol, 48, 990-1000 (2018)
  Pohl JM, Volke JK, Thiebes S, Brenzel A, Fuchs K, Beziere N, Ehrlichmann W, Pichler BJ, Squire A, Gueler F, Engel DR
  
• Proliferation of Ly6C+ monocytes during urinary tract infections is regulated by IL-6 trans-signaling. J Leukoc Biol, 1, 13-22 (2018)
  Dixit A, Bottek J, Beerlage AL, Schuettpelz J, Thiebes S, Brenzel A, Garbers C, Rose-John S, Mittrücker HW, Squire A, Engel DR
  
• Neutrophil biology in Chronic Lymphocytic Leukemia and infections
  Nirojah Vijitha
  
• Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder. Mucosal Immunol, 13, 702-714 (2020)
  Bottek J, Soun C, Lill JK, Dixit A, Thiebes S, Beerlage AL, Horstmann M, Urbanek A, Heuer H, Uszkoreit J, Eisenacher M, Bracht Th, Sitek B, Hoffmann F, Vijitha N, Eggeling F, Engel DR