Pathogenesis

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

Introduction:
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 projects:
Project 1.1:
The first project aims at defining the role of TIR8 and PTX3 in sepsis induced immunosuppression.

Project 1.2:
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

Introduction:
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.

The projects:
Project 1.3:
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.

Project 1.4:
This project will focus on identification of epigenetic signatures of immunosuppression of immune effector cells.

Project 1.5:
The last project in this WP will focus on linking the microRNAome with distinct septic transcriptional responses that characterize immunosuppression.