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.

Crosstalk of innate and adaptive immune cells is mediated by SYK and NLRP3 after SARS-CoV-2 vaccination. (A/B) Vaccination activates SYK coupled to C-type lectins, which activates the NRLP3 inflammasome. (C) Macrophage NLRP3 and IL-1β release drives T- cell activation and differentiation.

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).

Hypothetical model of influence of innate immune cells on adaptive immune response after SARS-CoV-2 vaccination.

Innate immune system and SARS-CoV-2 infection and vaccination (Illustration by Sandra Krahl)

Lab Website

For more information, please check the research website.

Affiliations - Jan Rybniker

Affiliations - Sebastian Theobald

Department I of Internal Medicine, Faculty of Medicine

Publication Record on PubMed - Jan Rybniker

Publication Record on PubMed - Sebastian Theobald

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024 (up to June)

Albert MC, Uranga-Murillo I, Arias M, De Miguel D, Pena N, Montinaro A, Varanda AB, Theobald SJ, Areso I, Saggau J, Koch M, Liccardi G, Peltzer N, Rybniker J, Hurtado-Guerrero R, Merino P, Monzon M, Badiola JJ, Reindl-Schwaighofer R, Sanz-Pamplona R, Cebollada-Solanas A, Megyesfalvi Z, Dome B, Secrier M, Hartmann B, Bergmann M, Pardo J, and Walczak H (2024). Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality. Cell Death Differ. doi:10.1038/s41418-024-01278-6.
Gries R, Chhen J, van Gumpel E, Theobald SJ, Sonnenkalb L, Utpatel C, Metzen F, Koch M, Dallenga T, Djaout K, Baulard A, Dal Molin M, and Rybniker J (2024). Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system. Cell Chem Biol31, 699-711 e696. doi:10.1016/j.chembiol.2023.12.007.
Hamdorf M, Imhof T, Bailey-Elkin B, Betz J, Theobald SJ, Simonis A, Di Cristanziano V, Gieselmann L, Dewald F, Lehmann C, Augustin M, Klein F, Alejandre Alcazar MA, Rongisch R, Fabri M, Rybniker J, Goebel H, Stetefeld J, Brachvogel B, Cursiefen C, Koch M, and Bock F (2024). The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm. J Mol Cell Biol15. doi:10.1093/jmcb/mjad062.
Knopf JD, Steigleder SS, Korn F, Kuhnle N, Badenes M, Tauber M, Theobald SJ, Rybniker J, Adrain C, and Lemberg MK (2024). RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling. Nat Commun15, 1528. doi:10.1038/s41467-024-45615-2.
Marner M, Kulhanek N, Eichberg J, Hardes K, Molin MD, Rybniker J, Kirchner M, Schaberle TF, and Gottlich R (2024). Design, synthesis and antimycobacterial activity of imidazo[1,5-a]quinolines and their zinc-complexes. RSC Med Chem15, 1746-1750. doi:10.1039/d4md00086b.
Suarez I, Rauschning D, Schuller C, Hagemeier A, Stecher M, Lehmann C, Schommers P, Schlabe S, Vehreschild JJ, Koll C, Schwarze-Zander C, Wasmuth JC, Klingmuller A, Rockstroh JK, Fatkenheuer G, Boesecke C, and Rybniker J (2024). Incidence and risk factors for HIV-tuberculosis coinfection in the Cologne-Bonn region: a retrospective cohort study. Infection. doi:10.1007/s15010-024-02215-y.

2023

Augustin M, Heyn F, Ullrich S, Sandaradura de Silva U, Albert MC, Linne V, Schlotz M, Schommers P, Pracht E, Horn C, Suarez I, Simonis A, Picard LK, Zoufaly A, Wenisch C, Fatkenheuer G, Gruell H, Klein F, Hallek M, Walczak H, Rybniker J, Theobald SJ, and Lehmann C (2023). Immunological fingerprint in coronavirus disease-19 convalescents with and without post-COVID syndrome. Front Med (Lausanne) 10, 1129288. doi:10.3389/fmed.2023.1129288.
Gries R, Chhen J, van Gumpel E, Theobald SJ, Sonnenkalb L, Utpatel C, Metzen F, Koch M, Dallenga T, Djaout K, Baulard A, Dal Molin M, and Rybniker J (2023). Discovery of dual-active ethionamide boosters inhibiting the Mycobacteriumtuberculosis ESX-1 secretion system. Cell Chem Biol. doi:10.1016/j.chembiol.2023.12.007.
Gries R, Dal Molin M, Chhen J, van Gumpel E, Dreyer V, Niemann S, and Rybniker J (2023). Characterization of Two Novel Inhibitors of the Mycobacterium tuberculosis Cytochrome bc(1) Complex. Antimicrob Agents Chemother 67, e0025123. doi:10.1128/aac.00251-23.
Hamdorf M, Imhof T, Bailey-Elkin B, Betz J, Theobald SJ, Simonis A, Di Cristanziano V, Gieselmann L, Dewald F, Lehmann C, Augustin M, Klein F, Alcazar MAA, Rongisch R, Fabri M, Rybniker J, Goebel H, Stetefeld J, Brachvogel B, Cursiefen C, Koch M, and Bock F (2023). The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm. J Mol Cell Biol. doi:10.1093/jmcb/mjad062.
Kretschmer AC, Junker L, Dewald F, Linne V, Hennen L, Horemheb-Rubio G, Kaiser R, Steger G, Joachim A, Schonenkorb J, Cosgun ZC, Muhlhans N, Heger E, Knops E, Leisse C, Kessel B, Heinsohn T, Rodiah I, Lange B, Ritter AL, Fries M, Kossow A, Niessen J, Dotsch J, Klein F, Rybniker J, Fatkenheuer G, and Suarez I (2023). Implementing the Lolli-Method and pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools: a pilot project. Infection 51, 459-464. doi:10.1007/s15010-022-01865-0.
Malin JJ, Suarez I, Biehl LM, Schommers P, Knops E, Di Cristanziano V, Heger E, Pflieger E, Wyen C, Bettin D, Rybniker J, Fatkenheuer G, and Lehmann C (2023). Immune response to mRNA-based COVID-19 booster vaccination in people living with HIV. HIV Med 24, 785-793. doi:10.1111/hiv.13481.
Simonis A, Kreer C, Albus A, Rox K, Yuan B, Holzmann D, Wilms JA, Zuber S, Kottege L, Winter S, Meyer M, Schmitt K, Gruell H, Theobald SJ, Hellmann AM, Meyer C, Ercanoglu MS, Cramer N, Munder A, Hallek M, Fatkenheuer G, Koch M, Seifert H, Rietschel E, Marlovits TC, van Koningsbruggen-Rietschel S, Klein F, and Rybniker J (2023). Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa. Cell 186, 5098-5113 e5019. doi:10.1016/j.cell.2023.10.002.
Theobald SJ, Fiestas E, Schneider A, Ostermann B, Danisch S, von Kaisenberg C, Rybniker J, Hammerschmidt W, Zeidler R, and Stripecke R (2023). Fully Human Herpesvirus-Specific Neutralizing IgG Antibodies Generated by EBV Immortalization of Splenocytes-Derived from Immunized Humanized Mice. Cells 13. doi:10.3390/cells13010020.
van Wijk RC, Lucia A, Sudhakar PK, Sonnenkalb L, Gaudin C, Hoffmann E, Dremierre B, Aguilar-Ayala DA, Molin MD, Rybniker J, de Giorgi S, Cioetto-Mazzabo L, Segafreddo G, Manganelli R, Degiacomi G, Recchia D, Pasca MR, Simonsson USH, Ramon-Garcia S, and consortium ET (2023). Implementing best practices on data generation and reporting of Mycobacterium tuberculosis in vitro assays within the ERA4TB consortium. iScience 26, 106411. doi:10.1016/j.isci.2023.106411.

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