Role of neutrophil polarization during Pseudomonas aeruginosa-induced sepsis in the immunocompromised host

• Applicant: Professorin Dr. Jadwiga Jablonska-Koch
• Subject Area: Immunology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279759388

Due to the growing number of immunocompromised people and their susceptibility to opportunistic infections with pathogens such as Pseudomonas aeruginosa it is of utmost importance to study mechanisms that lead to decreased immune responses in such a hosts. Majority of immunocompromised people consists of cancer patients, which can be both; solid tumor or leukemia bearing. Since neutrophil differentiation is altered in tumor bearing hosts and neutrophils are known to be essential for control of bacterial, e.g. P. aeruginosa infections, it is reasonable to predict that such variations in neutrophil differentiation are responsible for observed host susceptibility. To address this hypothesis we plan to perform mouse experiments as well as studies with patient derived specimen. It is of particular interest to address how neutrophil subsets are changed in immunocompromised (e.g. tumor bearing) versus normal mice, and how such changes impact the clearance of Pseudomonas infection. Our recent studies showed that characteristics of neutrophils are changed in tumor bearing hosts, depending on IFN-beta availability. Recently, TGF-beta was suggested to oppose action of type I IFN on neutrophils. To follow up this phenomenon we study if cytokines such as type I IFNs and TGF-beta influence neutrophil differentiation in a tumor free animals and how this altered differentiation influences P. aeruginosa infection. Furthermore, we will investigate which consequences such changes have on the immune responses against P. aeruginosa in tumor situation. Finally, observations will be translated to the human situation by measuring the capability of human neutrophils to kill Pseudomonas in vitro. Neutrophils isolated from healthy donors will be compared to neutrophils from tumor patients. To assess the role of type I IFNs in this setting, neutrophils from melanoma tumor patients treated and untreated with type I IFNs, will be compared. We expect to define diagnostic neutrophil markers that are associated with enhanced susceptibility to P. aeruginosa infection and markers that allow monitoring successful treatment of Pseudomonas infection in immunocompromised hosts.

• DFG Programme: Research Grants