Center for Molecular Medicine Cologne

Rybniker, Jan | Theobald, Sebastian - B 10

Deciphering and modulating innate and adaptive immune crosstalk in SARS-CoV-2 vaccination

Introduction

Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely currently applied SARS-CoV-2 vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Data from our recent publications show that both SARS-CoV-2 infection and vaccination prime human macrophages for activation of the NLRP3 inflammasome. Furthermore, we identified spleen tyrosine kinase (SYK) as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein specific T cell responses. In addition, vaccination induced macrophage priming can be enhanced with repetitive antigen exposure, providing a rationale for prime-boost concepts to augment immune signaling and crosstalk. Our study aims to further improve our understanding of the exact role and impact of innate immune cell signaling in shaping the immune response following vaccination. In a comprehensive approach, we will exploit ex vivo and in vivo models to activate inflammasomes with different adjuvants and vaccine constructs targeting toll-like receptors (TLR) and C-type lectins. Using autologous co-culture experiments with cell subsets of the adaptive immune system, we will systematically determine the impact of innate immune signaling on the quantity and quality of long-lived anti-viral immunity. These data will be of high relevance for future vaccine constructs, choice of adjuvants and vaccination regimen targeting SARS-CoV-2 and other viral pathogens.

Figure 1

Clinical Relevance

The frequent occurrence of new SARS-CoV-2 variants-of-concern renders the existing vaccines less effective, highlighting the urgent need for improved strategies. Within this project, we seek to exploit our recent discoveries on the role of innate immune cell signaling in SARS-CoV-2 vaccine immunogenicity. We aim to evaluate the value of tailored inflammasome priming for improved vaccination schemes in comprehensive ex vivo and in vivo approaches. Improving vaccine-induced innate immune responses can also have strong implications for vaccine development against other pathogen and even tumor vaccines.

    Approach

    • WP 1: Analysis of the inflammatory pathways of the innate immune system and consequences for the adaptive immunity induced by SARS-CoV-2 infection and mRNA vaccination using novel in vitro and ex vivo model systems
    • WP 2: In vivo analysis of innate and adaptive immune responses using classical knockout models and novel humanized mice models.
    • WP 3: Optimization of immunization strategies by specifically modulating innate immune sensing and activation followed by in vivo efficacy testing (surrogate markers of protection).
    Figure 2
    Figure 3
    • Theobald et al., Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19, EMBO Mol Med. 2021 Aug 9;13(8):e14150. doi: 10.15252/emmm.202114150.
    • Eisfeld et al., Viral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages, Viruses. 2021 Oct 15;13(10):2076. doi: 10.3390/v13102076.
    • Theobald et al., Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination. EMBO Mol Med. 2022 Aug 8;14(8):e15888. doi: 10.15252/emmm.202215888.
    • Theobald et al., Monocyte-crosstalk drives interferon-mediated signaling following SARS-CoV-2 exposure., Mol Syst Biol. 2022 Sep;18(9):e11256. doi: 10.15252/msb.202211256.
    Prof. Dr. Dr. Jan Rybniker CMMC Cologne
    Prof. Dr. Dr. Jan Rybniker

    Clinic I of Internal Medicine & Center for Molecular Medicine Cologne - CMMC Research Building

    CMMC - PI - B 10
    CMMC - former PI - CAP 08

    Publications - Jan Rybniker

    Link to PubMed

    Publications - Sebastian Theobald

    Link to PubMed

    Affiliations - Sebastian Theobald

     

    Group Members

    PostDocs
    Dr. Michael Dal Molin
    Dr. Jakob Malin
    Dr. Lea Picard
    Priv.-Doz. Dr. Isabelle Suàrez

    PhD students
    Julie Mudler
    Dinah Lange
    Raphael Gries

    Master student
    Jasmine Decker
    Katharina Keck

    Medical student
    Hannah Eisfeld
    Technicians
    Sandra Winter
    Edeltraud van Gumpel
    Jason Chhen

    Visiting scientist
    Dr. Claudius Gottschalk