Involved partners: Lead Beneficiary: Istituto Clinico Humanitas (ICH)
Other participants: AMC, UoA, CHUV, BIOC, GEN, bMx
The main objective of this workpackage is to describe the pathogenesis of sepsis-induced immune suppression at the level of immune regulatory molecules and DNA methylation. This includes to try and
- define the role of key molecules involved in regulation of inflammatory responses in the pathogenesis of sepsis induced immunosuppression (PTX3, TIR8/SIGIRR, IRAK-M).
- define DNA methylation marks that associate to, and influence, the immune suppression phenotype among sepsis patients.
Below these projects are described in a bit more detail:
Defining the role of molecules involved in regulation of inflammatory responses
Pentraxin 3 (PTX3) was originally identified by ICH to be produced at sites of infection and inflammation by both somatic and immune cells. The expression of PTX3 is rapidly induced in a variety of cells by several stimuli, such as cytokines and bacteria. PTX3 may be involved both in the early hyperinflammatory or late compensatory anti-inflammatory phase of the septic response. IL-1R-associated-kinase (IRAK)-M and TIR8/SIGIRR are thought to also be directly related to infection, the latter being a molecule acting intra-cellularly to inhibit IL-1R like receptors and Toll-like receptor (TLR) signalling, originally cloned by ICH and associated with infections, (e.g. tuberculosis, candidiasis, Pseudomonas aeruginosa.
The first project aims at defining the role of TIR8 and PTX3 in sepsis induced immunosuppression.
The second project focuses on the role of IRAK-M which has emerged as a key player in sepsis induced immunosuppression.
Defining DNA methylation marks
Recent studies have indicated that epigenetic mechanisms may be an important driving force behind sepsis-associated immunosuppression. The unprecedented large data set from the well-characterised sepsis patients in the MARS cohort (link/ref?) will be used to elaborate on this relationship.
This project will focus on mapping genome-wide DNA methylation patterns that impact on the disturbed transcriptional responses that associate to sepsis-induced immune suppression.
This project will focus on identification of epigenetic signatures of immunosuppression of immune effector cells.
The last project in this WP will focus on linking the microRNAome with distinct septic transcriptional responses that characterize immunosuppression.