Bacterial Load as a Driver of Immune and Neutrophil Dysfunction in Sepsis

• Applicant: Dr. Philipp Joschua Gebhard Mathe
• Subject Area: Clinical Infectiology and Tropical Medicine ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574058222

Sepsis is a life-threatening condition triggered by a dysregulated immune response to infection. Emerging evidence suggests that not only the presence of a pathogen but, in particular, the bacterial load is a key factor in the pathophysiology of sepsis. The BactImmune study investigates the hypothesis that a high bacterial burden leads to overstimulation of the innate immune system, which in turn triggers dysregulation of immune defense mechanisms, contributing to the development of both hyperinflammation and immunosuppression. The aim of the study is to characterize in detail the relationship between bacterial load, immune response, and neutrophil dysfunction in patients with sepsis. The focus lies especially on the early phases of sepsis—those critical time windows in which clinical and immunological decisions have the greatest impact on disease progression. The three main objectives (work packages, WP) of the study are: 1. WP1 – Measurement and comparison of bacterial load quantification methods: Various techniques (e.g., time-to-positivity, digital PCR, viability PCR, PAMP detection) will be systematically compared to assess their predictive value for clinical outcomes such as mortality, organ dysfunction, and septic shock. 2. WP2 – Definition of sepsis-specific endotypes based on bacterial load: Using transcriptomic and proteomic profiling (RNA sequencing, Olink panels), the study will evaluate whether different bacterial loads are associated with distinct immunological patterns ("endotypes") that can be distinguished both clinically and molecularly. 3. WP3 – Analysis of neutrophil phenotypes in relation to bacterial load: The study will investigate whether and how varying bacterial loads influence the composition and function of neutrophil subpopulations (e.g., G-MDSCs). This will involve flow cytometry, cytokine assays, and phagocytosis function testing. The project builds on and extends an existing prospective cohort at the University Medical Center Freiburg, in which blood samples are collected within the first hours of clinical deterioration. This unique early sampling approach enables precise analysis of dynamic immunological changes. Based on the data obtained, the study aims to identify novel biomarkers for risk stratification and potential therapeutic targets for personalized immune modulation.

• DFG Programme: Research Grants