The Cellular Response Capacity of Neutrophil Granulocytes as a Novel Immunomonitoring Approach in Endotoxemia and Sepsis

• Applicant: Privatdozent Dr. David Messerer
• Subject Area: Clinical Infectiology and Tropical Medicine ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545061513

Sepsis is a life-threatening disease with a high individual and socioeconomic burden. It is characterized by a dysregulated host response to infection, often resulting in organ dysfunction, shock, and death. Early identification of sepsis and the initiation of sepsis treatment are of paramount importance in reducing mortality and morbidity, as timely intervention greatly improves patient outcomes. However, the rapid diagnosis and appropriate monitoring of the sepsis-related immune response remain an unmet clinical need. This research project focuses on a novel immunomonitoring method termed Cellular Response Capacity (CRC). The CRC will be applied to monitor neutrophil granulocytes as the most abundant leukocytes with a high turnover using flow cytometry, which has not yet been translated into clinical routine. Among others, standardization is a major translational roadblock. Based on the development of a cell-based fixpoint, which is independent of previous stimulation by pathogens, the research project aims to generate standardized ratios. These ratios will be used for the multiparametric analysis of sepsis-associated changes in neutrophils, which alter their phenotype more rapidly upon contact with pathogens. These distinct alterations - in conjunction with measurement of these changes in a highly standardized manner by using the CRC - are hypothesized to respond more rapidly to pathogen exposure in comparison to traditional humoral biomarkers of inflammation such as interleukin 6 or procalcitonin, which become positive with a relevant delay, among other reasons, due the protein biosynthesis. The research project hypothesizes that the CRC of neutrophils outperforms conventional humoral biomarkers of inflammation in I) the diagnosis of endotoxemia and bacteremia ex vivo and II) the monitoring of the sepsis-related inflammation in clinical sepsis. The first part of the project will identify neutrophil surface antigens and corresponding measurement techniques, which are suitable for the CRC, together with the optimization of further methodological aspects. The ex vivo trials will involve experimental endotoxemia and bacteremia in a concentration- and time-dependent manner in human blood, providing crucial data on the performance of the CRC under standardized conditions. The in realiter part will focus on patients with sepsis, allowing a comprehensive assessment of CRC's potential benefits over traditional immunomonitoring approaches. In summary, this research project will develop, analyze, and validate the CRC immunomonitoring method. The CRC of neutrophils is hypothesized to outperform conventional humoral biomarkers of inflammation in diagnosing endotoxemia and sepsis as well as in monitoring the sepsis associated inflammatory response and thereby will potentially revolutionize sepsis diagnosis and monitoring for improved patient outcomes.

• DFG Programme: Research Grants