Center for Molecular Medicine Cologne

Rybniker, Jan - assoc. RG 32

Innate immunity in host-pathogen interactions

Introduction

The group mainly focusses on novel treatment strategies to augment the defense mechanisms of the host against viral and bacterial pathogens. A main activity the laboratory involves timely processing of patient material in several bedside-to-bench studies. We also exploit high throughput molecular techniques for antimicrobial drug discovery for which we have established modern equipment such as pipetting robots and liquid handling systems in our BSL2 and BSL3 laboratories at the Center for Molecular Medicine Cologne. Since the emergence of COVID-19, we have studied the impact of SARS-COV-2 infection and vaccination on the innate immune system. Our activities are directed at translational research with the ultimate goal of improving patient wellbeing.

Identification of novel compounds with antibacterial properties

The emergence of multidrug resistant bacteria is a major public health concern with increased morbidity and mortality throughout the world. In addition to the search for novel antibiotics, alternative approaches, such as the development of anti-virulence drugs and adjunctive host directed therapies are necessary to fill the antibiotic gap that appeared in the past decade. Our group has focused on multidrug resistant Mycobacterium tuberculosis (Mtb) for which we have developed a drug screening platform that is capable of combining all three approaches in a single assay. Proof of concept studies identified novel Mtb-specific antibiotics, anti-virulence drugs targeting a mycobacterial secretion system, and host directed therapies with novel mode of action. We have extended our innovative screening method to highly drug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa (Pa) and Salmonella enterica serovar Typhimurium (ST) by exploiting their type 3 secretion system (T3SS) dependent host cell killing. Here we could identify several substances showing promising effects on Pa and ST pathogenicity that will provide the basis for future pre-clinical and clinical development with the ultimate goal of tackling the looming antibiotic resistance crisis.

Innate and adaptive immune crosstalk in COVID-19

Our lab has taken part in the worldwide efforts to improve our understanding of COVID-19 and to develop possible treatment and vaccination strategies. More than two and a half years since the occurrence of the first COVID-19 cases, the pandemic is still far from over. The frequent occurrence of new SARS-CoV-2 variants-of-concern renders the existing vaccines less effective, highlighting the urgent need for improved strategies. 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 (Figure 1). Importantly, our data show that vaccination induced macrophage priming can be enhanced with repetitive antigen exposure. In further studies, we would like to systematically determine the influence of the innate immune system on the quantity and quality of long-lived antiviral immunity. These data will be important for the development of future vaccines and vaccination regimens against SARS-CoV-2 and other viral pathogens.

  • Rybniker J, Vocat A, Sala C, Busso P, Pojer F, Benjak A, Cole ST. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015;6:7659
  • Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, Schmid-Burgk JL, Schmidt T, Hornung V, Cole ST, Ablasser A. Mycobacterium tuberculosis differentially activates cgas- and inflammasome-dependent intracellular immune responses through esx-1. Cell Host Microbe. 2015;17:799-81
  • Rybniker J, Chen JM, Sala C, Hartkoorn RC, Vocat A, Benjak A, Boy-Rottger S, Zhang M, Szekely R, Greff Z, Orfi L, Szabadkai I, Pato J, Keri G, Cole ST. Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion. Cell Host Microbe. 2014;16:538-548
  • Lechartier B, Rybniker J, Zumla A, Cole ST. Tuberculosis drug discovery in the post-post-genomic era. EMBO Mol Med. 2014;6:158-168 (shared first authorship)
  • Rybniker J, Pojer F, Marienhagen J, Kolly GS, Chen JM, van Gumpel E, Hartmann P, Cole ST. The cysteine desulfurase iscs of mycobacterium tuberculosis is involved in iron-sulfur cluster biogenesis and oxidative stress defence. Biochem J. 2014;459:467-478
  • Chen JM, Zhang M, Rybniker J, Boy-Rottger S, Dhar N, Pojer F, Cole ST. Mycobacterium tuberculosis espb binds phospholipids and mediates esxa-independent virulence. Mol Microbiol. 2013;89:1154-1166
  • Rybniker J, Nowag A, Janicki H, Demant K, Hartmann P, Buning H. Incorporation of antigens into viral capsids augments immunogenicity of adeno-associated virus vector-based vaccines. J Virol. 2012;86:13800-13804
  • Rybniker J, Krumbach K, van Gumpel E, Plum G, Eggeling L, Hartmann P. The cytotoxic early protein 77 of mycobacteriophage l5 interacts with msmeg_3532, an l-serine dehydratase of mycobacterium smegmatis. J Basic Microbiol. 2011;51:515-522
  • Dewald F, Suarez I, Johnen R, Grossbach J, Moran-Tovar R, Steger G, Joachim A, Rubio GH, Fries M, Behr F, Kley J, Lingnau A, Kretschmer A, Gude C, Baeza-Flores G, Del Valle DL, Roblero-Hernandez A, Magana-Cerino J, Hernandez AT, Ruiz-Quinones J, Schega K, Linne V, Junker L, Wunsch M, Heger E, Knops E, Di Cristanziano V, Meyer M, Hunseler C, Weber LT, Luers JC, Quade G, Wisplinghoff H, Tiemann C, Zotz R, Jomaa H, Pranada A, Herzum I, Cullen P, Schmitz FJ, Philipsen P, Kirchner G, Knabbe C, Hellmich M, Buess M, Wolff A, Kossow A, Niessen J, Jeworutzki S, Schrapler JP, Lassig M, Dotsch J, Fatkenheuer G, Kaiser R, Beyer A, Rybniker J, and Klein F (2022). Effective high-throughput RT-qPCR screening for SARS-CoV-2 infections in children. Nat Commun13, 3640. doi:10.1038/s41467-022-30664-2.
  • Malin JJ, Di Cristanziano V, Horn C, Pracht E, Garcia Borrega J, Heger E, Knops E, Kaiser R, Boll B, Lehmann C, Jung N, Borchmann P, Fatkenheuer G, Klein F, Hallek M,and Rybniker J (2022). SARS-CoV-2-neutralizing antibody treatment in patients with COVID-19 and immunodeficiency due to B-cell non-Hodgkin lymphoma. Blood Adv6, 1580-1584. doi:10.1182/bloodadvances.2021006655.
  • Eisfeld HS, Simonis A, Winter S, Chhen J, Stroh LJ, Krey T, Koch M, Theobald SJ, and Rybniker J (2021). Viral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages. Viruses13. doi:10.3390/v13102076.
  • Heyckendorf J, Marwitz S, Reimann M, Avsar K, DiNardo AR, Gunther G, Hoelscher M, Ibraim E, Kalsdorf B, Kaufmann SHE, Kontsevaya I, van Leth F, Mandalakas AM, Maurer FP, Muller M, Nitschkowski D, Olaru ID, Popa C, Rachow A, Rolling T, Rybniker J, Salzer HJF, Sanchez-Carballo P, Schuhmann M, Schaub D, Spinu V, Suarez I, Terhalle E, Unnewehr M, Weiner J, 3rd, Goldmann T, and Lange C (2021). Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model. Eur Respir J58. doi:10.1183/13993003.03492-2020.
  • Horn C, Augustin M, Ercanoglu MS, Heger E, Knops E, Bondet V, Duffy D, Chon SH, Nierhoff D, Oette M, Schafer H, Vivaldi C, Held K, Anderson J, Geldmacher C, Suarez I, Rybniker J, Klein F, Fatkenheuer G, Muller-Trutwin M, and Lehmann C (2021). HIV DNA reservoir and elevated PD-1 expression of CD4 T-cell subsets particularly persist in the terminal ileum of HIV-positive patients despite cART. HIV Med22, 397-408. doi:10.1111/hiv.13031.
  • Joachim A, Dewald F, Suarez I, Zemlin M, Lang I, Stutz R, Marthaler A, Bosse HM, Lubke N, Munch J, Bernard MA, Jeltsch K, Tonshoff B, Weidner N, Krausslich HG, Birzele L, Hubner J, Schmied P, Meyer-Buhn M, Horemheb-Rubio G, Cornely OA, Haverkamp H, Wiesmuller G, Fatkenheuer G, Hero B, Kaiser R, Dotsch J, Rybniker J, and group BFs (2021). Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial. EClinicalMedicine39, 101082. doi:10.1016/j.eclinm.2021.101082.
  • Theobald SJ, Grab J, Fritsch M, Suarez I, Eisfeld HS, Winter S, Koch M, Holscher C, Pasparakis M, Kashkar H, and Rybniker J (2021). Gasdermin D mediates host cell death but not interleukin-1beta secretion in Mycobacterium tuberculosis-infected macrophages. Cell Death Discov7, 327. doi:10.1038/s41420-021-00716-5.
  • Theobald SJ, Simonis A, Georgomanolis T, Kreer C, Zehner M, Eisfeld HS, Albert MC, Chhen J, Motameny S, Erger F, Fischer J, Malin JJ, Grab J, Winter S, Pouikli A, David F, Boll B, Koehler P, Vanshylla K, Gruell H, Suarez I, Hallek M, Fatkenheuer G, Jung N, Cornely OA, Lehmann C, Tessarz P, Altmuller J, Nurnberg P, Kashkar H, Klein F, Koch M, and Rybniker J (2021). Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med13, e14150. doi:10.15252/emmm.202114150.
  • Warnat-Herresthal S, Schultze H, Shastry KL, Manamohan S, Mukherjee S, Garg V, Sarveswara R, Handler K, Pickkers P, Aziz NA, Ktena S, Tran F, Bitzer M, Ossowski S, Casadei N, Herr C, Petersheim D, Behrends U, Kern F, Fehlmann T, Schommers P, Lehmann C, Augustin M, Rybniker J, Altmuller J, Mishra N, Bernardes JP, Kramer B, Bonaguro L, Schulte-Schrepping J, De Domenico E, Siever C, Kraut M, Desai M, Monnet B, Saridaki M, Siegel CM, Drews A, Nuesch-Germano M, Theis H, Heyckendorf J, Schreiber S, Kim-Hellmuth S, Study C-A, Nattermann J, Skowasch D, Kurth I, Keller A, Bals R, Nurnberg P, Riess O, Rosenstiel P, Netea MG, Theis F, Mukherjee S, Backes M, Aschenbrenner AC, Ulas T, Deutsche C-OI, Breteler MMB, Giamarellos-Bourboulis EJ, Kox M, Becker M, Cheran S, Woodacre MS, Goh EL, and Schultze JL (2021). Swarm Learning for decentralized and confidential clinical machine learning. Nature594, 265-270. doi:10.1038/s41586-021-03583-3.
  • Simonis A, Theobald SJ, Fatkenheuer G, Rybniker J, and Malin JJ (2021). A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2. EMBO Mol Med13, e13105. doi:10.15252/emmm.202013105.
  • Augustin M, Schommers P, Suarez I, Koehler P, Gruell H, Klein F, Maurer C, Langerbeins P, Priesner V, Schmidt-Hellerau K, Malin JJ, Stecher M, Jung N, Wiesmuller G, Meissner A, Zweigner J, Langebartels G, Kolibay F, Suarez V, Burst V, Valentin P, Schedler D, Cornely OA, Hallek M, Fatkenheuer G, Rybniker J, and Lehmann C (2020). Rapid response infrastructure for pandemic preparedness in a tertiary care hospital: lessons learned from the COVID-19 outbreak in Cologne, Germany, February to March 2020. Euro Surveill 25.
  • Bacher P, Rosati E, Esser D, Martini GR, Saggau C, Schiminsky E, Dargvainiene J, Schroder I, Wieters I, Khodamoradi Y, Eberhardt F, Vehreschild M, Neb H, Sonntagbauer M, Conrad C, Tran F, Rosenstiel P, Markewitz R, Wandinger KP, Augustin M, Rybniker J, Kochanek M, Leypoldt F, Cornely OA, Koehler P, Franke A, and Scheffold A (2020). Low-Avidity CD4(+) T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19. Immunity 53, 1258-71 e5.
  • Bernardes JP, Mishra N, Tran F, Bahmer T, Best L, Blase JI, Bordoni D, Franzenburg J, Geisen U, Josephs-Spaulding J, Kohler P, Kunstner A, Rosati E, Aschenbrenner AC, Bacher P, Baran N, Boysen T, Brandt B, Bruse N, Dorr J, Drager A, Elke G, Ellinghaus D, Fischer J, Forster M, Franke A, Franzenburg S, Frey N, Friedrichs A, Fuss J, Gluck A, Hamm J, Hinrichsen F, Hoeppner MP, Imm S, Junker R, Kaiser S, Kan YH, Knoll R, Lange C, Laue G, Lier C, Lindner M, Marinos G, Markewitz R, Nattermann J, Noth R, Pickkers P, Rabe KF, Renz A, Rocken C, Rupp J, Schaffarzyk A, Scheffold A, Schulte-Schrepping J, Schunk D, Skowasch D, Ulas T, Wandinger KP, Wittig M, Zimmermann J, Busch H, Hoyer BF, Kaleta C, Heyckendorf J, Kox M, Rybniker J, Schreiber S, Schultze JL, Rosenstiel P, Network HCALB, and Deutsche C-OI (2020). Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19. Immunity 53, 1296-314 e9.
  • Di Cristanziano V, Meyer-Schwickerath C, Eberhardt KA, Rybniker J, Heger E, Knops E, Hallek M, Klein F, Holtick U, and Jung N (2020). Detection of SARS-CoV-2 viremia before onset of COVID-19 symptoms in an allo-transplanted patient with acute leukemia. Bone marrow transplantation 10.1038/s41409-020-01059-y.
  • Eberhardt KA, Meyer-Schwickerath C, Heger E, Knops E, Lehmann C, Rybniker J, Schommers P, Eichenauer DA, Kurth F, Ramharter M, Kaiser R, Holtick U, Klein F, Jung N, and Di Cristanziano V (2020). RNAemia Corresponds to Disease Severity and Antibody Response in Hospitalized COVID-19 Patients. Viruses 12.
  • Gries R, Sala C, and Rybniker J (2020). Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection. Appl Sci-Basel 10.
  • Holscher C, Grab J, Holscher A, Muller AL, Schafer SC, and Rybniker J (2020). Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice. Sci Rep 10, 13629.
  • Hos NJ, Fischer J, Hos D, Hejazi Z, Calabrese C, Ganesan R, Murthy AMV, Rybniker J, Kumar S, Kronke M, and Robinson N (2020). TRIM21 Is Targeted for Chaperone-Mediated Autophagy during Salmonella Typhimurium Infection. J Immunol 205, 2456-67.
  • Malin JJ, Suarez I, Priesner V, Fatkenheuer G, and Rybniker J (2020b). Remdesivir against COVID-19 and Other Viral Diseases. Clinical microbiology reviews 34.
  • Rybniker J, and Fatkenheuer G (2020). Importance of precise data on SARS-CoV-2 transmission dynamics control. Lancet Infect Dis 10.1016/S1473-3099(20)30359-5.
  • Suarez I, Gruell H, Heyckendorf J, Funger S, Lichtenstein T, Jung N, Lehmann C, Unnewehr M, Fatkenheuer G, Lange C, and Rybniker J (2020a). Intensified adjunctive corticosteroid therapy for CNS tuberculomas. Infection 48, 289-93.
  • von Amburen J, Schreiber F, Fischer J, Winter S, van Gumpel E, Simonis A, and Rybniker J (2020). Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium. Microorganisms 8.
PD Dr. Dr. Jan Rybniker CMMC Cologne
PD Dr. Dr. Jan Rybniker

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

CMMC - PI - assoc. RG 32

CMMC - former PI - CAP 08

+49 221 478 89611

+49 221 478 5915

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

Robert-Koch-Str. 21

50931 Cologne

https://innere1.uk-koeln.de/forschung/arbeitsgruppen-labore/translational-research-unit-infectious-diseases/ag-bacterial-pathogenesis-and-antibiotic-drug-discovery-en/

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Curriculum Vitae (CV)

Publications - Jan Rybniker

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