Celluloepidemiology: a novel paradigm for modeling T-cell responses on a population level.

Información del proyecto

CELLULO-EPI

Identificador del acuerdo de subvención: 851752

DOI

10.3030/851752

Proyecto cerrado

Fecha de la firma de la CE 12 Febrero 2020

Fecha de inicio 1 Marzo 2020

Fecha de finalización 31 Agosto 2025

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 499 734,00

Aportación de la UE

€ 1 499 734,00

Coordinado por

UNIVERSITEIT ANTWERPEN
Belgium

Periodic Reporting for period 4 - CELLULO-EPI (Celluloepidemiology: a novel paradigm for modeling T-cell responses on a population level.)

Período documentado: 2024-09-01 hasta 2025-08-31

Resumen del contexto y de los objetivos generales del proyecto

Celluloepidemiology is a term invented to describe an interdisciplinary approach combining unique cellular immune responses against pathogens on a population level with mathematical modeling, thereby generating unique and otherwise not obtainable multidimensional T-cell profiles.

CELLULO-EPI will develop and use such a highly innovative model to simulate how T-cells against pathogens evolve in a synthetic population as a function of age, gender, time since infection and other relevant variables. This model will be parameterized and fitted by cross sectional T-cell data against a wide set of pathogens from 500 individuals (sampled again after 1 year), unique data from individuals with known first infections with chikungunya and longitudinal data from individuals receiving de novo yellow fever vaccination or re-exposed to chickenpox.

The insights of CELLULO-EPI will be pivotal for public health. One important example: Varicella-zoster virus (VZV) causes chickenpox but also shingles after VZV reactivation. Vaccination can prevent chickenpox, but the predicted increase in shingles incidence has blocked chickenpox vaccination in many EU-countries. Indeed, re-exposure to chickenpox is hypothesized to protect against shingles through boosting of T-cells. Unfortunately, none of the available epidemiological or immunological tools allow for adequate validation of the boosting hypothesis. However, CELLULO-EPI will be able to solve this persisting VZV vaccination dilemma. Furthermore, CELLULO-EPI will also redefine infectious disease epidemiology, for example by allowing us to back-calculate the time since last exposure.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We have been able to recruit > 600 participants and obtained PBMC and serum from these individuals.
- We have analysed a large cohort of > 600 participants for which we performed cytof mass cytometry to obtain best T-cell markers to analyse T-cell responses against SARS-CoV-2, VZV and parvovirus B19.
- We used these markers on a novel flow cytometer allowing in-depth high-throughput T-cell characterization for more than 600 samples (each 5 stimuli).
- We developed a R based program (including automatic gating) allowing us to appropriately and timely analyse these 3000 flow cytometry data files using the Flemish Super Computer.
- We used FLOWSOM (again supported by the Flemish Super Computer) to define T-cell subclusters.
- We used machine learning algorithms to infer fundamental immunological differences between the different population groups regarding SARS-CoV-2
- We developed mathematical models, based on agent-based models, to simulate VZV and B19 specific T cell responses throughout time
- We obtained multi-omics data that allowed defining clusters of individuals depending on different variables including CMV serostatus and faecal microbiome
- We have shown that CMV seropositivity is associated with senescent T cells
- We have shown that antigen-specific immunity declines with ageing
- We have shown that individuals with high exposure to various infections have a higher VZV-specific T cell responses
- We have shown that de novo yellow fever vaccination induces both CD4+ and CD8+ T cell responses with changing T cell phenotypes

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

- we have been able to show that T-cell based epidemiology might be a validate alternative for antibody based epidemiology
- we have shown that T cell based epidemiology can indicate the severity of the SARS-CoV-2 infection in health care workers
- we have shown that T cell receptor data modeling can differentiate individuals with recent SARS-CoV-2 infection from individuals with only common coronavirus exposure
- we have shown that certain faecal microbiome clusters are associated with less inflammation
- we have shown that even > 3 months after SARS-CoV-2 infection a higher inflammatory state remains in these convalescent patients
- we have shown that interrogation of blood TCR repertoires can indicate the faecal microbiome
- we have shown that integrative agent-based modeling can adequately simulate the T cell response against VZV and B19

ERC