From the pathophysiological point of view, this project proposal will look at the role of human MDSCs in severe bacterial and fungal infections.Results obtained potentially can contribute in the design of immunomodulatory therapy of sepsis
Sepsis is a very severe complication of bacterial, fungal or viral infections that affects an estimated 19 million persons each year. It is characterized by a high mortality of up to 28-50% in the developed world and most likely much higher in poor resource settings. Sepsis mortality was considered to be the consequence of overwhelming activation of immune cells, resulting in inflammation-driven tissue injury. Recently, it has become apparent that infection triggers a much more complex host response, with concurrent activation of pro- and anti-inflammatory mechanisms. Immune suppression has recently been implicated as a key driver of mortality in sepsis. T cell receptor dysfunction followed by apoptosis of CD4+ T cells and TH2 polarization are important hallmarks of immune suppression in sepsis. Myeloid derived suppressor cells (MDSCs) potently interfere with T cell biology, namely inducing migratory arrest, apoptosis, insufficient TCR expression and signaling as well as targeted expansion of Tregs.
Sepsis is associated with a state of immunoparalysis, wherein the ability of MDSCs to inhibit immune responses by using a large array of different mechanisms might be a major feature. This project addresses the scarce evidence for the well-known, but poorly understood immune suppression in sepsis patients, as well as our lack of understanding the mechanisms underlying the effect of MDSCs in sepsis clinical evolution and treatment outcome. The overall hypothesis of this proposal is that MDSCs expansion plays a crucial role in sepsis-induced immunoparalysis, and that this might represent an important potential therapeutic target. Understanding these mechanisms will inform MDSC-centered host directed therapy approaches in human sepsis. We propose a study based on experimental cell-based approaches. The results observed in vitro will be validated on MDSCs directly isolated from 50 - 100 bacterial and fungal sepsis cases
To identify the mechanisms regulating human MDSCs expansion during bacterial and fungal sepsis and characterize MDSCs role in sepsis-induced immunoparalysis.
- Phenotype, morphology, function and cytokine production capacity of MDSCs isolated from sepsis patients and healthy controls
- Identification of sepsis-induced transcriptome in MDSCs compared with various relevant human cell populations.
- Validation of pathway and gene targets previously identified, on MDSCs isolated from sepsis patients.
- Bio bank of sample sets for further study.
Teaching Assistant STREAȚĂ IOANA – Project manager
Professor MIHAI G. NETEA – Mentor