Deciphering stem cell immunity

Informazioni relative al progetto

STEMGUARD

ID dell’accordo di sovvenzione: 101075865

DOI

10.3030/101075865

Data della firma CE 12 Giugno 2023

Data di avvio 1 Agosto 2023

Data di completamento 31 Luglio 2028

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 500 000,00

Contributo UE

€ 1 500 000,00

Coordinato da

INSTITUT CURIE
France

Periodic Reporting for period 1 - STEMGUARD (Deciphering stem cell immunity)

Periodo di rendicontazione: 2023-08-01 al 2026-01-31

Sintesi del contesto e degli obiettivi generali del progetto

Stem cells are essential for maintaining tissue integrity throughout life. Their ability to self-renew and differentiate makes them indispensable for regeneration and repair. Yet, despite their central role, stem cells are highly vulnerable to both exogenous threats—such as viral infections—and endogenous ones, including transposable elements (TEs) that can disrupt genomic stability. Intriguingly, stem cells do not rely on classical immune pathways like interferon signaling, which are active in differentiated cells. This raises a fundamental question: what guards the guardians?

Recent discoveries, including the identification of the antiviral protein aviD—a stem cell-specific isoform of Dicer—have revealed that stem cells deploy unique, poorly understood immune mechanisms. aviD mediates antiviral RNA interference (RNAi), protecting stem cells from RNA viruses such as Zika and SARS-CoV-2. Preliminary data also suggest aviD may silence TEs, a function potentially shared with cancer cells that express stemness-like transcriptional programs.

The STEMGUARD project aims to (1) dissect the aviD-driven antiviral pathway in vivo, (2) explore aviD’s role in TE silencing and its implications for cancer immunity, and (3) discover entirely new stem cell-specific immune mechanisms using genome-wide and bioinformatics-driven approaches.

By unveiling how stem cells defend themselves, STEMGUARD will redefine our understanding of innate immunity and open new therapeutic avenues. In cancer, where TE silencing dampens immune responses, targeting aviD or RNAi could awaken immunogenicity and enhance anti-tumour therapies. The project’s interdisciplinary nature—bridging virology, stem cell biology, cancer immunology, and bioinformatics—positions it to make a transformative impact on both fundamental science and clinical innovation.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Aims 1 and 2 of STEMGUARD are on-going. Within Aim 3 of the STEMGUARD project, we developed and implemented a novel bioinformatics pipeline to identify previously uncharacterized immune proteins in humans by leveraging evolutionary conservation with bacterial antiphage systems. This approach was based on the hypothesis that certain antiviral mechanisms in bacteria are conserved in eukaryotes, including stem cells. In collaboration with the Bernheim team (Institut Pasteur), we performed large-scale comparative analyses between bacterial antiphage systems and the human and mouse genomes. Using sequence homology, phylogenetic profiling, and expression data mining, we shortlisted candidate human proteins with no known immune function, conserved across species. This reverse comparative immunology strategy led to the identification of several novel human genes with antiviral activity. The project thus established a proof-of-concept for discovering immune mechanisms through cross-domain evolutionary analysis.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The STEMGUARD project pioneers a novel approach to immune discovery by leveraging evolutionary conservation across domains of life. While previous studies have retrospectively linked known human immune pathways to bacterial antiphage systems—such as the cGAS/STING pathway to CBASS—STEMGUARD reverses this logic. It implements a bioinformatics pipeline to identify previously uncharacterized human proteins by comparing them to recently discovered bacterial antiviral systems. This forward-looking strategy enables the prediction of immune functions in human proteins that lack prior annotation, thus expanding the known repertoire of innate immunity.

The project goes beyond state of the art by integrating phylogenetic analysis, protein homology, and expression profiling to isolate candidates that are conserved between bacteria and humans, and devoid of known immune roles. This cross-kingdom comparative immunology is unprecedented in its scale and specificity. The method has already yielded novel human immune factors, validating the approach. It opens avenues of research on the targeting of novel immune proteins in immunotherapies, both in cancer and autoimmune pathologies.