Publications by authors named "Philipp Georg"

8 Publications

  • Page 1 of 1

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment.

Cell 2020 09 5;182(6):1419-1440.e23. Epub 2020 Aug 5.

Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL).

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRCD11c inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405822PMC
September 2020

SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.

Nature 2020 11 29;587(7833):270-274. Epub 2020 Jul 29.

Si-M/'Der Simulierte Mensch', Technische Universität Berlin and Charité-Universitätsmedizin Berlin, Berlin, Germany.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4 T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4 T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4 T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.
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http://dx.doi.org/10.1038/s41586-020-2598-9DOI Listing
November 2020

Noncoding RNA is an integral component of the TLR4-TRIF pathway.

Proc Natl Acad Sci U S A 2020 04 2;117(16):9042-9053. Epub 2020 Apr 2.

Institute for Lung Research, Philipps-University, 35043 Marburg, Germany;

RNA has been proposed as an important scaffolding factor in the nucleus, aiding protein complex assembly in the dense intracellular milieu. Architectural contributions of RNA to cytosolic signaling pathways, however, remain largely unknown. Here, we devised a multidimensional gradient approach, which systematically locates RNA components within cellular protein networks. Among a subset of noncoding RNAs (ncRNAs) cosedimenting with the ubiquitin-proteasome system, our approach unveiled ncRNA as a critical structural component of the Toll-like receptor 4 (TLR4) immune signal transduction pathway. RNA affinity antisense purification-mass spectrometry (RAP-MS) revealed binding to optineurin (OPTN), a ubiquitin-adapter platforming TBK1 kinase. binding stabilized OPTN, and consequently, loss of blunted OPTN aggregation, TBK1-dependent IRF3 phosphorylation, and type I interferon (IFN) gene transcription downstream of TLR4. expression was elevated in patients with active pulmonary infection and was highly correlated with IFN levels in bronchoalveolar lavage fluid. Our study uncovers as an integral RNA component of the TLR4-TRIF pathway and predicts further RNAs to be required for assembly and progression of cytosolic signaling networks in mammalian cells.
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http://dx.doi.org/10.1073/pnas.1920393117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183186PMC
April 2020

Innate sensors that regulate vaccine responses.

Curr Opin Immunol 2019 08 9;59:31-41. Epub 2019 Apr 9.

Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

Pattern recognition receptors (PRRs) control elemental functions of antigen presenting cells (APCs) and critically shape adaptive immune responses. Wielding a natural adjuvanticity, live attenuated vaccines elicit exceptionally efficient and durable immunity. Commonly used vaccine adjuvants target individual PRRs or bolster the immunogenicity of vaccines via indirect mechanisms of inflammation. Here, we review the impact of innate sensors on immune responses to live attenuated vaccines and commonly used vaccine adjuvants, with a focus on human vaccine responses. We discuss the unique potential of microbial nucleic acids and their corresponding sensing receptors to mimic live attenuated vaccines and promote protective immunity.
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http://dx.doi.org/10.1016/j.coi.2019.02.006DOI Listing
August 2019

Recognition of microbial viability via TLR8 drives T cell differentiation and vaccine responses.

Nat Immunol 2018 04 19;19(4):386-396. Epub 2018 Mar 19.

Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (T cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting T cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust T cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of T cell differentiation and a promising target for T cell-skewing vaccine adjuvants.
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http://dx.doi.org/10.1038/s41590-018-0068-4DOI Listing
April 2018

Toxicological risk at workplace and toxicity as Life Cycle Assessment impact category: Substitution of solvents as an example.

EXCLI J 2017 10;16:40-51. Epub 2017 Jan 10.

ALGURA Chemie GmbH Co KG, Handwerkerstraße 12, D-48720 Rosendahl, Germany.

Substitution of hazardous substances against less hazardous ones is a central requirement of the European Chemical Regulation REACH (European Regulation 1907/2006/EC). Hazardous substances emitted from products may not only affect the worker; drift off and distribution in the environment may finally result in exposure of the general population. This potential threat to health is covered by the impact category "toxicity" in Life Cycle Assessments. In this paper, we present a case of a substitution of volatile organic compounds in a reactive varnish, and compare the "old" formulation with the "new" formulation against health risk to the worker, and concerning the Life Cycle Assessment impact category "toxicity". The "old" formulation contained Naphtha (petroleum), hydrodesulfurized, heavy and Solvent naphtha (petroleum), light, aromatic. In the new formulation, both naphthas were replaced by n-Butylacetate, 1-Ethoxy-2-propyl acetate and Ethyl-3-ethoxy propionate. In the European Union, the naphthas are classified as mutagens and carcinogens category 1, officially. However, if benzene is below 0.1 %, registrants in the EU proposed to omit this classification, and todays naptha products on the market obviously have benzene contents below 0.1 %. On a first glance, the improvement for workplace safety introduced by the substitution, therefore, is comparatively small, as it is for toxicity in Life Cycle Assessment. However, when background knowledge concerning chemical production processes of naphtha is included, benzene below a content of 0.1 % needs to be taken into consideration, and the benefit of substitution is more obvious.
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http://dx.doi.org/10.17179/excli2016-764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318680PMC
January 2017

Pathogen-triggered activation of plasmacytoid dendritic cells induces IL-10-producing B cells in response to Staphylococcus aureus.

J Immunol 2013 Feb 16;190(4):1591-602. Epub 2013 Jan 16.

Department of Infectious Diseases, Medical Microbiology, and Hygiene, University Hospital Heidelberg, D-69120 Heidelberg, Germany.

Induction of polyclonal B cell activation is a phenomenon observed in many types of infection, but its immunological relevance is unclear. In this study we show that staphylococcal protein A induces T cell-independent human B cell proliferation by enabling uptake of TLR-stimulating nucleic acids via the V(H)3(+) BCR. We further demonstrate that Staphylococcus aureus strains with high surface protein A expression concomitantly trigger activation of human plasmacytoid dendritic cells (pDC). Sensitivity to chloroquine, cathepsin B inhibition, and a G-rich inhibitory oligodeoxynucleotide supports the involvement of TLR9 in this context. We then identify pDC as essential cellular mediators of B cell proliferation and Ig production in response to surface protein A-bearing S. aureus. The in vivo relevancy of these findings is confirmed in a human PBMC Nod/scid(Prkdc)/γc(-/-) mouse model. Finally, we demonstrate that co-operation of pDC and B cells enhances B cell-derived IL-10 production, a cytokine associated with immunosuppression and induction of IgG4, an isotype frequently dominating the IgG response to S. aureus. IL-10 release is partially dependent on TLR2-active lipoproteins, a hallmark of the Staphylococcus species. Collectively, our data suggest that S. aureus exploits pDC and TLR to establish B cell-mediated immune tolerance.
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http://dx.doi.org/10.4049/jimmunol.1201222DOI Listing
February 2013

Plasmacytoid dendritic cells control B cell-derived IL-10 production.

Autoimmunity 2012 Dec 17;45(8):579-83. Epub 2012 Sep 17.

Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany.

Plasmacytoid dendritic cells (pDC) exert contradictory roles: they represent major players in the pathogenesis of type I interferon-mediated autoimmunity but contribute to tolerance in the transplant setting. In this study we describe pDC as cellular enhancers of B cell-derived IL-10 production, a mechanism recently described as relevant in maintaining peripheral tolerance. Our data demonstrate that in human peripheral blood pDC augment IL-10 production in B cells in response to TLR7 and -9 ligands. They further show that pDC themselves produce IL-10 in response to TLR stimulation, most prominently after triggering of TLR7. Additionally, the data indicate that the positive regulatory effect of pDC on IL-10 production is not due to type I interferon production or other soluble factors. We conclude that pDC/B cell contact is essential for B cell-mediated immune suppression.
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http://dx.doi.org/10.3109/08916934.2012.719955DOI Listing
December 2012