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Die Rolle der Neutrophilen Polarisierung während Pseudomonas aeruginosa-induzierter Sepsis im immunsupprimierten Wirt

Fachliche Zuordnung Immunologie
Förderung Förderung von 2015 bis 2021
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 279759388
 
Erstellungsjahr 2021

Zusammenfassung der Projektergebnisse

In this project, we set out to determine the role of tumor-associated neutrophils in the susceptibility of immunosupressed individuals to Pseudomonas aeruginosa sepsis. We could demonstrate that growing tumors significantly impact the phenotype, functionality and activity of neutrophils in tumor-bearing hosts. Moreover, type I IFN system seems to play a role in this process as tumor-associated neutrophils from IFN-deficient animals seems to have strong protumor bias, including elevated survival, elevated migratory capacity and strong pro-angiogenic capacity. Such pro-tumoral neutrophils support also efficiently metastatic processes by the accumulation in target organs and expressing S100A8 and S100A9 that attract tumor cells. Importantly, we could observe that the lack of type I IFN signaling support expression of G- CSF – growth factor strongly involved in the regulation of neutrophil activity. The mechanisms behind this process should be further investigated. Next to their tumorigenic activity, neutrophils in tumor-bearing hosts show also altered antibacterial capacity. We could demonstrate that neutrophils isolated from tumor-bearing mice, but also from tumor patients show decreased anti-bacterial properties, such as phagocytosis, NETs formation and ROS release. At the same time these neutrophils seem to exert strong cytotoxic capacity towards epithelial cells. We have found that high G-CSF levels released by tumor lead to the prominent neutrophil infiltration in the lungs and significant alterations of neutrophil activity. These changes lead to the prominent tissue damage and the persistence of Pseudomonas aeruginosa in the lung. Restoring the balance between antibacterial and tissue-damaging properties could serve as an additional way of prevention or treatment of the bacterial complications in patients with cancer. Moreover, screening for G-CSF levels in cancer-bearing individuals may be considered as a tool to determine the patients with high predisposition to bacterial complications. In the context of type I IFNs, we could unexpectedly observe that IFN-deficient tumor-free animals are less susceptible for Pseudomonas aeruginosa infections, in comparison to their WT counterparts. Importantly, in spite of their important role in the activation of immune system, type I interferons stimulate neutrophils to release NETs that are subsequently used by the bacteria to create biofilms that support Pseudomonas to better survive in the lungs of the host. Moreover, such NETs participate in the damage of the lung tissue due to the presence of histones and proteolytic enzymes in such structures. All together, the activation of neutrophils by type I IFNs was mainly harmful for the host, not protective, which was the unexpected result of our studies. We plan to further evaluate mechanisms regulating neutrophil anti-bacterial activity in tumor bearing hosts and expand our studies on other bacterial strains, different infection models and tumors. All these results should lead to better understanding of the mechanisms that regulate bactericidal functions of neutrophils in cancer patients, but will also identify factors that may be targeted therapeutically to support antibacterial neutrophil functions in such patients. This could provide a novel therapeutic strategy for the treatment of cancer patients who are prone to develop infection-associated complications during, or after, therapy as a result of impaired neutrophil activity.

Projektbezogene Publikationen (Auswahl)

 
 

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