Work packages

This page presents a high-level overview of the different work packages within the ESA programme

› European Sepsis Academy › ESA Work Packages

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.

DISCOVERY

Involved partners: Lead Beneficiary: Centre Hospitalier Universitaire Vaudois (CHUV)

Other participants: UoA, ICH, bMx, INSEAD, UCL, LUM BIOC

The main objective of this workpackage is to identify and validate biomarkers that can be used for clinical diagnosis and monitoring of sepsis-induced immune suppression. This can be divided in three separate projects:

Dynamic profile of myeloid-derived suppressor cells (MDSC) in sepsis
Defining whether defined immune regulatory molecules are potential biomarkers.
To explore the hypothesis that sepsis-related immune suppression is a consequence of bioenergetic dysfunction and can be used as sepsis biomarker.Below these projects are described in a bit more detail:

Dynamic profile of myeloid-derived suppressor cells (MDSC) in sepsis

Introduction:
Overall, experimental models have clearly demonstrated that sepsis-induced MDSC suppress inflammatory responses and protect from lethal infection. Yet, owing to their powerful immunosuppressive properties, MDSC may play a central role in the development of the protracted immunosuppressive phase of sepsis, especially adaptive immunosuppression. Our objective is to deeply characterise MDSC subpopulations in septic patients with the ultimate goal to settle whether monitoring blood MDSC will be useful for follow-up of septic patients.

The projects:
Project 2.1:
The most up-to-date technologies will be used to assess the expression and the heterogeneity of MDSC in our ongoing cohort of culture confirmed sepsis patients admitted to the ICU compared to healthy controls.

Project 2.2:
Fluidigm and CyTOF analyses will provide a unique view of the heterogeneity and possibly the ontogeny and developmental relationship of MDSC subpopulations.

Defining whether defined immune regulatory molecules are potential biomarkers.

Introduction:
Here we aim to validate
(a) the diagnostic and prognostic potential of PTX3 in sepsis, in particular in the stratification of patients and in monitoring stage of sepsis
(b) the hypothesis that TIR8 may be a marker of the anti-inflammatory phase of the septic response
(c) the hypothesis that IL-1R2 may be a marker of the anti-inflammatory phase of the septic response
(d) test tools to be developed (e.g. mAb and ELISA) in order to evaluate the relevance of MSF as marker of regulatory monocytes/macrophages in sepsis.

The projects:
Project 2.3:
We aim to evaluate and validate discovered biomarkers for early prognostic stratification of septic patients.

Bioenergetic dysfunction

Introduction:
The pathophysiological mechanisms underlying multiple organ dysfunction in sepsis remain to be fully elucidated, however there is increasing evidence that bioenergetic dysfunction (mitochondrion dysfunction) plays a major role. Multiple studies from UCL and others demonstrate (i) biochemical and histological mitochondrial abnormalities in sepsis patients, animal and cell models, and (ii) a temporal relationship between restoration of mitochondrial functionality, improvement in organ function and clinical recovery. In various laboratory models of sepsis, cells, organs or whole animals can be protected by treatments aimed at either mitochondrial protection, e.g. using mitochondrial-targeted antioxidants, or at enhancing recovery of functioning mitochondria through stimulating biogenesis. We intend to explore the hypothesis that bioenergetic dysfunction is a key mechanism underlying immune suppression in sepsis. This will be performed using samples taken from patients, from animal models, and from healthy cells incubated in septic serum.

The projects:
Project 2.4:
This project aims at studying the bioenergetic function and immune suppression in leukocyte subsets in experimental sepsis and critically ill septic patients.

Project 2.5:
Here we aim to correct the bioenergetic dysfunction using mitochondrial-targeted therapies to restore immune functionality.

DEVELOPMENT

Involved partners: Lead Beneficiary: Biomerieux (bMx)

Other participants: UCL, LUM, CHUV, GEN, ICH, INSEAD, AMC

The main objective of this workpackage is to prepare and optimise high-potential diagnostic technology platforms for use in diagnostic procedures in sepsis and to evaluate new clinical trial designs. This can be divided in two separate projects:

To optimise innovative immune functional assays that would be suitable to monitor the immune status and the risk of nosocomial infections of patients in critical conditions
To evaluate these prototypes in a pilot clinical study
To evaluate the sequential clinical trial design in sepsis research

Below these projects are described in a bit more detail:

Defining the role of molecules involved in regulation of inflammatory responses

Introduction:
The ESA-ITN project will make it possible to develop and standardize immune functional assays that are better suited to the constraints of the clinical hospital setting and particularly those of critical care conditions.

The projects:
Project 3.1:
This project aims to optimize new immune functional assay techniques to better characterize monocyte and lymphocyte anergy observed in septic patients and conform to the constraints of the hospital setting.

Project 3.2:
Taking the clinical context of sepsis and ICU into account, the global objective of this project will be to provide a prototype system allowing the digitalization and standardization of ex vivo immune functional assays at single-cell level using droplet-based microfluidics for studying single cells.

To evaluate these prototypes in a pilot clinical study

Introduction:
Molecular signatures derived from blood leukocytes provide more information about the nature and severity of the inflammatory response and the magnitude of organ injury than traditional single protein or gene biomarkers. These signatures can be used for identifying patients at risk of dying and/or sepsis complications, thereby allowing individualised preventive or therapeutic interventions.

The projects:
Project 3.3:
The main objective of this project is to identify molecular signatures within blood leukocytes, with three aims:
(1) to quantitate sepsis induced immunosuppression,
(2) to identify patients at high risk of developing (hospital-acquired) sepsis after ICU admission
(3) to stratify the individual patient with respect to risk of dying.

To evaluate the sequential clinical trial design in sepsis research

Introduction:
The problem of clinical trial design in sepsis are diverse. For example, patients enter sequentially and may receive one of two treatments (control or novel therapy arm). The rewards might be quantified by clinical benefit minus some function of cost of therapy. From patient to patient, the rewards may differ due to normal random variation. Parameters of the mean patient benefit may be unknown and are inferred (e.g. the presence or absence of biomarkers). The “big data” movement in data analytics has brought covariates that depend on patient characteristics into the picture. Similarly, recent work in stochastic simulation optimisation to incorporate Gaussian process regression and Bayesian value of information approaches to sequential sampling has reduced the number of samples required to identify the best alternative quickly.

The projects:
Project 3.4:
This project will build on our prior work in sequential modelling to
(1) adapt the Bayesian value of information approach for selecting the best stochastic alternative to the context of sequential clinical trials
(2) to use the Gaussian process regression model to extend the aggregation concept of Rigollet and Zeevi (2010) to potentially improve the use of continuous-valued diagnostic data
(3) to design a clinical trial algorithm based on the above results to allow for a small set of covariates to be accounted for in a clinical trial design
(4) to use a simulation study to allow for the new sequential clinical trial design to be compared with existing trial designs.

Project 3.5:
This project will be a collaboration of network partners at INSEAD, AMC, CHUV and ICH to make computer code (Matlab or R) of the mathematical development of the previous project, as well as computer code representing more classical approaches to clinical trial design.

TRAINING

2016:

As an introduction, we had our very successful kick-off meeting in conjunction with the International Sepsis Forum (ISF)’s 9th Annual Symposium, December 6-8 2016 in Paris at the Institut Pasteur. This way all ESRs had a proper introduction in the world of sepsis.

2017:

AMC organized a very successful congress in collaboration with our partner ESCMID: SEPSIS 2017: From Pathogenesis to Treatment. This event was organized June 1-3 2017 in Amsterdam and it was an EACCME accredited event
CHUV organized the Immunology Summer School, an intensive one-week training in immunology focusing on the biology of the immune system and its role in health and disease, in Lausanne 4-8 September 2017, that was attended by all ESRs.
All ESRs attended our second consortium meeting which we organized during ISF/ESS SEPSIS2017, September 13-15, 2017 in Paris, in between the annual conference organized by the International Sepsis Forum and the European Shock Society (ESS).

2018:

Advanced Course on ‘How to develop diagnostic tests and commercialize these?, March 26-28, 2018, at Mérieux University, Marcy lÉtoile, France
followed by the ESA-ITN Research Course on ‘Immune Functional Assays/IFA’ was organized at bioMérieux, March 29, 2018.
INSEAD organized a very thorough and succesful summerschool (mini-MBA), July 2-6, 2018, in Fontainebleau, France.
Hands on intensive care unit (ICU) course, London, 12-14 September 2018, London at the ICU of UCL

2019:

Sepsis biomarker development, organized by the European Sepsis Academy with the UoA and in conjunction with the Hellenic Sepsis Society, Athens, October 2019.
Final MSCA ITN ESA meeting: achievements and perspectives. Crete, Greece. October 9th 2019

MANAGEMENT

Involved partners: Lead Beneficiary: Academic medical centre Amsterdam (AMC)

Other participants: all, TTOP

Introduction:

The Workpackage objectives are:

a) To establish and maintain a transparent and effective management framework that will support the project governing structure and activities

b) To monitor progress of the ESRs, tasks and obtained results within the defined time and budget plan and taking actions pro-actively when required

c) To guarantee compliance with the Consortium Grant Agreement

d) To ensure optimal awareness and exploitation of the project results

The Projects:

Task 5.1: Project coordination and governance:
This task comprises the setup of all bodies of the management structure, including Supervisory Board, Management Team, Graduate School, Advisory Board, Board of Fellows and WPLs. Furthermore, coordination involves the organization of (network) meetings, the preparation and follow-up by editing documents in support of the meetings, writing minutes and circulating information to members.

Task 5.2: Establishing consortium communication tools:
A secured collaboration portal will be set up, which will be designed specifically to optimize communication between the consortium partners. The portal will also be used as a site to distribute documents of general use to the consortium.

Task 5.3: Dissemination and exploitation:
Throughout the project upon achievement of particular outcomes, deliverables or milestones, publications of results will be issued.

Task 5.4: IP protection and exploitation of consortium results:
All results obtained within the consortium will be carefully evaluated and protected before any public dissemination. The consortium partners will share access to knowledge generated during the project according to the fundamental intellectual property rules as defined in the grant agreement.

Task 5.5: Reporting
The EC requires regular reporting on the deliverables as well as annual financial and technical progress reports. In close collaboration with the WP leaders reports will be prepared for each deliverable for submission to the EC. Financial reporting comprises preparing and sending financial reports to the EC. Yearly, a technical report will be prepared including a publishable summary of the progress of work towards the objectives of the project, achievements and attainment of any milestones and deliverables.

“This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 676129. This website reflects only the author’s view and the European Commission is not responsible for any use that may be made of the information it contains”