المؤلفون: Tabea M. Eser, Olga Baranov, Manuel Huth, Mohammed I. M. Ahmed, Flora Deák, Kathrin Held, Luming Lin, Kami Pekayvaz, Alexander Leunig, Leo Nicolai, Georgios Pollakis, Marcus Buggert, David A. Price, Raquel Rubio-Acero, Jakob Reich, Philine Falk, Alissa Markgraf, Kerstin Puchinger, Noemi Castelletti, Laura Olbrich, Kanika Vanshylla, Florian Klein, Andreas Wieser, Jan Hasenauer, Inge Kroidl, Michael Hoelscher, Christof Geldmacher

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-13 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. Here, we perform a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We find that soluble and transcriptional markers of systemic inflammation peak during the first week after symptom onset and correlate directly with upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4+ and CD8+ T cells correlate inversely with various inflammatory markers and UA-VLs. In addition, we show that high frequencies of activated CD4+ and CD8+ T cells are present in acutely infected nasopharyngeal tissue, many of which express genes encoding various effector molecules, such as cytotoxic proteins and IFN-γ. The presence of IFNG mRNA-expressing CD4+ and CD8+ T cells in the infected epithelium is further linked with common patterns of gene expression among virus-susceptible target cells and better local control of SARS-CoV-2. Collectively, these results identify an immune correlate of protection against SARS-CoV-2, which could inform the development of more effective vaccines to combat the acute and chronic illnesses attributable to COVID-19.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/4dc5d871135c41fe9339d69cb0120fceTest

المؤلفون: Leo Nicolai, Karin Schiefelbein, Silvia Lipsky, Alexander Leunig, Marie Hoffknecht, Kami Pekayvaz, Ben Raude, Charlotte Marx, Andreas Ehrlich, Joachim Pircher, Zhe Zhang, Inas Saleh, Anna-Kristina Marel, Achim Löf, Tobias Petzold, Michael Lorenz, Konstantin Stark, Robert Pick, Gerhild Rosenberger, Ludwig Weckbach, Bernd Uhl, Sheng Xia, Christoph Andreas Reichel, Barbara Walzog, Christian Schulz, Vanessa Zheden, Markus Bender, Rong Li, Steffen Massberg, Florian Gaertner

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-4 (2022)

مصطلحات موضوعية: Science

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/ed292487695f4934991736364329901eTest

المؤلفون: Kami Pekayvaz, Alexander Leunig, Rainer Kaiser, Markus Joppich, Sophia Brambs, Aleksandar Janjic, Oliver Popp, Daniel Nixdorf, Valeria Fumagalli, Nora Schmidt, Vivien Polewka, Afra Anjum, Viktoria Knottenberg, Luke Eivers, Lucas E. Wange, Christoph Gold, Marieluise Kirchner, Maximilian Muenchhoff, Johannes C. Hellmuth, Clemens Scherer, Raquel Rubio-Acero, Tabea Eser, Flora Deák, Kerstin Puchinger, Niklas Kuhl, Andreas Linder, Kathrin Saar, Lukas Tomas, Christian Schulz, Andreas Wieser, Wolfgang Enard, Inge Kroidl, Christof Geldmacher, Michael von Bergwelt-Baildon, Oliver T. Keppler, Mathias Munschauer, Matteo Iannacone, Ralf Zimmer, Philipp Mertins, Norbert Hubner, Michael Hoelscher, Steffen Massberg, Konstantin Stark, Leo Nicolai

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-21 (2022)

مصطلحات موضوعية: Science

الوصف: Infection with SARS-COV-2 can result in self-limited upper airway infection or progress to a more systemic inflammatory condition including pneumonic COVID-19. Here the authors utilise a multi-omics approach to interrogate the immune response of patients with self-limiting upper respiratory SARS-CoV-2 infection and reveal a temporal immune trajectory they associate with viral containment and restriction from pneumonic progressive disease.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/25f8c8382ab44535bbd9a714a216c8f8Test

المؤلفون: Leo Nicolai, Karin Schiefelbein, Silvia Lipsky, Alexander Leunig, Marie Hoffknecht, Kami Pekayvaz, Ben Raude, Charlotte Marx, Andreas Ehrlich, Joachim Pircher, Zhe Zhang, Inas Saleh, Anna-Kristina Marel, Achim Löf, Tobias Petzold, Michael Lorenz, Konstantin Stark, Robert Pick, Gerhild Rosenberger, Ludwig Weckbach, Bernd Uhl, Sheng Xia, Christoph Andreas Reichel, Barbara Walzog, Christian Schulz, Vanessa Zheden, Markus Bender, Rong Li, Steffen Massberg, Florian Gaertner

المصدر: Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020)

مصطلحات موضوعية: Science

الوصف: Breakdown of vascular barriers is a major complication of inflammatory diseases. However, the mechanisms underlying platelet recruitment to inflammatory micro-environments remains unclear. Here, the authors identify haptotaxis as a key effector function of immune-responsive platelets

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/4823a6cec2a1460586e33e31ba7a0aefTest

المؤلفون: Leo Nicolai, Rainer Kaiser, Raphael Escaig, Marie-Louise Hoffknecht, Afra Anjum, Alexander Leunig, Joachim Pircher, Andreas Ehrlich, Michael Lorenz, Hellen Ishikawa-Ankerhold, William C. Aird, Steffen Massberg, Florian Gaertner

المصدر: Haematologica, Vol 107, Iss 7 (2021)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Visualizing cell behavior and effector function on a single cell level has been crucial for understanding key aspects of mammalian biology. Due to their small size, large number and rapid recruitment into thrombi, there is a lack of data on fate and behavior of individual platelets in thrombosis and hemostasis. Here we report the use of platelet lineage restricted multi-color reporter mouse strains to delineate platelet function on a single cell level. We show that genetic labeling allows for single platelet and megakaryocyte (MK) tracking and morphological analysis in vivo and in vitro, while not affecting lineage functions. Using Cre-driven Confetti expression, we provide insights into temporal gene expression patterns as well as spatial clustering of MK in the bone marrow. In the vasculature, shape analysis of activated platelets recruited to thrombi identifies ubiquitous filopodia formation with no evidence of lamellipodia formation. Single cell tracking in complex thrombi reveals prominent myosin-dependent motility of platelets and highlights thrombus formation as a highly dynamic process amenable to modification and intervention of the acto-myosin cytoskeleton. Platelet function assays combining flow cytrometry, as well as in vivo, ex vivo and in vitro imaging show unaltered platelet functions of multicolor reporter mice compared to wild-type controls. In conclusion, platelet lineage multicolor reporter mice prove useful in furthering our understanding of platelet and MK biology on a single cell level.

وصف الملف: electronic resource

العلاقة: https://haematologica.org/article/view/10406Test; https://doaj.org/toc/0390-6078Test; https://doaj.org/toc/1592-8721Test

الوصول الحر: https://doaj.org/article/43e3282e3a9f488895e15ffcec411f2eTest

المؤلفون: Rainer Kaiser, Alexander Leunig, Kami Pekayvaz, Oliver Popp, Markus Joppich, Vivien Polewka, Raphael Escaig, Afra Anjum, Marie-Louise Hoffknecht, Christoph Gold, Sophia Brambs, Anouk Engel, Sven Stockhausen, Viktoria Knottenberg, Anna Titova, Mohamed Haji, Clemens Scherer, Maximilian Muenchhoff, Johannes C. Hellmuth, Kathrin Saar, Benjamin Schubert, Anne Hilgendorff, Christian Schulz, Stefan Kääb, Ralf Zimmer, Norbert Hübner, Steffen Massberg, Philipp Mertins, Leo Nicolai, Konstantin Stark

المصدر: JCI Insight, Vol 6, Iss 18 (2021)

مصطلحات موضوعية: COVID-19, Vascular biology, Medicine

الوصف: Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry–based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8–CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8–like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein–induced, human ACE2–dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil–IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/6c76effe0be0417985fb0f08c49e4b8cTest

المؤلفون: Kami Pekayvaz, Alexander Leunig, Rainer Kaiser, Markus Joppich, Sophia Brambs, Aleksandar Janjic, Oliver Popp, Daniel Nixdorf, Valeria Fumagalli, Nora Schmidt, Vivien Polewka, Afra Anjum, Viktoria Knottenberg, Luke Eivers, Lucas E. Wange, Christoph Gold, Marieluise Kirchner, Maximilian Muenchhoff, Johannes C. Hellmuth, Clemens Scherer, Raquel Rubio-Acero, Tabea Eser, Flora Deák, Kerstin Puchinger, Niklas Kuhl, Andreas Linder, Kathrin Saar, Lukas Tomas, Christian Schulz, Andreas Wieser, Wolfgang Enard, Inge Kroidl, Christof Geldmacher, Michael von Bergwelt-Baildon, Oliver T. Keppler, Mathias Munschauer, Matteo Iannacone, Ralf Zimmer, Philipp Mertins, Norbert Hubner, Michael Hoelscher, Steffen Massberg, Konstantin Stark, Leo Nicolai

المصدر: Nature Communications

مصطلحات موضوعية: Adult, Male, T-Lymphocytes, General Physics and Astronomy, chemical and pharmacologic phenomena, General Biochemistry, Genetics and Molecular Biology, Monocytes, Nasopharynx, Ambulatory Care, Humans, Gene Regulatory Networks, Longitudinal Studies, Aged, Aged, 80 and over, Multidisciplinary, SARS-CoV-2, COVID-19, General Chemistry, biochemical phenomena, metabolism, and nutrition, Middle Aged, Killer Cells, Natural, Gene Expression Regulation, Cardiovascular and Metabolic Diseases, Cytokines, Female, Interferons, Technology Platforms

الوصف: The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment. We see a distinct systemic rather than local immune state associated with viral containment, characterized by interferon stimulated gene (ISG) upregulation across circulating immune cell subsets in non-pneumonic SARS-CoV2 infection. We report reduced cytotoxic potential of Natural Killer (NK) and T cells, and an immune-modulatory monocyte phenotype associated with protective immunity in COVID-19. Together, we show protective immune trajectories in SARS-CoV2 infection, which have important implications for patient prognosis and the development of immunomodulatory therapies.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6868e3511307cae2a86591340303a260Test
https://pubmed.ncbi.nlm.nih.gov/35197461Test

المؤلفون: Karsten Spiekermann, Konstantin Stark, Raphael Escaig, Steffen Massberg, Anna Titova, Alexander Leunig, Vivien Polewka, Dario Rossaro, Leo Nicolai, Luke Eivers, Afra Anjum, Marie-Louise Hoffknecht, Rainer Kaiser, Kami Pekayvaz, Eva Riedlinger, Matteo Iannacone

مصطلحات موضوعية: biology, business.industry, Spleen, medicine.disease_cause, Autoimmunity, medicine.anatomical_structure, Immune system, In vivo, Immunology, medicine, biology.protein, Platelet, Platelet activation, Antibody, Intramuscular injection, business

الوصف: Summary paragraphVaccines against SARS-CoV-2 are based on a range of novel vaccine platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently a rare and novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged: thrombosis with thrombocytopenia syndrome (TTS). TTS is characterized by low platelet counts, clot formation at unusual anatomic sites and platelet-activating PF4-polyanion antibodies reminiscent of heparin-induced thrombocytopenia. Here, we employ in vitro and in vivo models to characterize the possible mechanisms of this platelet-targeted autoimmunity. We show that intravenous but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation. After intravenous injection, these aggregates are phagocytosed by macrophages in the spleen and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of TTS and highlights accidental intravenous injection as potential mechanism for post-vaccination TTS. Hence, safe intramuscular injection, with aspiration prior to injection, could be a potential preventive measure when administering adenovirus-based vaccines.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::e087e8559e1b50438b17dff51547bb57Test
https://doi.org/10.1101/2021.06.29.450356Test

المؤلفون: Inge Kroidl, Kathrin Saar, Clemens Scherer, Norbert Huebner, Christoph Gold, Maximilian Muenchhoff, Vivien Polewka, Flora Deak, Rainer Kaiser, Wolfgang Enard, Oliver T. Keppler, Alexander Leunig, Leo Nicolai, Christof Geldmacher, Sophia Brambs, Aleksandar Janjic, Lukas Tomas, Lucas E. Wange, Johannes C. Hellmuth, Christian Schulz, Niklas Kuhl, Ralf Zimmer, Andreas Linder, Michael Hölscher, Philip Mertins, Kami Pekayvaz, Michael von Bergwelt-Baildon, Tabea M. Eser, Steffen Massberg, Markus Joppich, Oliver Popp, Konstantin Stark, Marieluise Kirchner

مصطلحات موضوعية: biology, business.industry, Interferon-stimulated gene, Disease, Immune system, Interferon, Stimulator of interferon genes, Immunology, biology.protein, Medicine, Cytotoxic T cell, Antibody, business, medicine.drug, Cohort study

الوصف: The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients.We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls.We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In vitro experiments show that Stimulator of Interferon Genes (STING) agonist treatment of PBMCs recapitulates the identified protective immunological signature and might therefore offer a novel therapeutic approach in early disease, without being affected by previously described anti-interferon antibodies. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction. Funding: This study was supported by the Deutsche Herzstiftung e.V., Frankfurt a.M. [LN],Deutsche Forschungsgemeinschaft (DFG) SFB 914 (S.M. [B02 and Z01], K.S. [B02]), the DFG SFB 1123 (S.M. [B06], K.S. [A07]), M.J and R.Z [Z02]), the DFG FOR 2033 (S.M.), the DGF SFB1243 (W.E., L.E.W. [A14], the DGF EN 1093/2-1 (W.E., A.J.), the German Centre for Cardiovascular Research (DZHK) (Clinician Scientist Programme [L.N.], MHA 1.4VD [S.M.]), DZIF MD student programme (TI 07.003_Deak [F.D.]), FP7 program (project 260309, PRESTIGE [S.M.]), FoFoLe project 1015/1009 (L.N.), and the DFG Clinician Scientist Programme PRIME (413635475, K.P., R.K.). The work was also supported by the European Research Council (ERC 2018-ADG “IMMUNOTHROMBOSIS” [S.M.] and ERC- “T-MEMORE” [K.S.])The CORKUM cohort study was supported by LMUexcellent, funded by the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Lander.The Koco19-Immu Study is funded by Bavarian State Ministry of Science and the Arts, University Hospital, LMU Munich, Helmholtz Centre Munich, University of Bonn, University of Bielefeld, German Ministry for Education and Research (Project No.: 01KI20271). Conflict of Interest: The authors declare no conflict of interest. Ethical Approval: In accordance with the Declaration of Helsinki, and with the approval of the Ethics Committee of Ludwig-Maximilian University Munich, informed consent of the patients or their guardians was obtained. COVID-19 patients are part of the COVID-19 Registry of the LMU University Hospital Munich (CORKUM, WHO trial ID DRKS00021225). Pseudonymizeddata was used for analysis, the CORKUM and KocoImmu studies were approved by the ethics committee of LMUMunich (No: 20-245 & No: 20-371 respectively).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::35f8ba15243adaf52679a241adad6b85Test
https://doi.org/10.1101/2021.02.03.429351Test

المؤلفون: Heiko Schulz, Maximilian Muenchhoff, Johannes C. Hellmuth, Saskia von Stillfried, Oliver T. Keppler, Rainer Kaiser, Marie-Louise Hoffknecht, Steffen Massberg, Markus Joppich, Stefan Kääb, Peter Boor, Adrian Ruhle, Ralf Zimmer, Konstantin Stark, Roman D. Bülow, Bernhard Zwißler, Stephan Ledderose, Kami Pekayvaz, Sophia Brambs, Clemens Scherer, Tobias Weinberger, Michael von Bergwelt-Baildon, Anouk Engel, Michael Zoller, Martina Rudelius, Vivien Polewka, Leo Nicolai, Christoph Gold, Alexander Leunig

المصدر: Journal of Thrombosis and Haemostasis
Journal of thrombosis and haemostasis : JTH 19(2), 574-581 (2021). doi:10.1111/jth.15179

مصطلحات موضوعية: Vasculitis, Chemokine, Neutrophils, Population, immunothrombosis, 030204 cardiovascular system & hematology, SARS‐CoV‐2, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Immune system, COVID‐19, Predictive Value of Tests, Immunopathology, Influenza, Human, medicine, immunopathology, Humans, education, Lung, ORIGINAL ARTICle, education.field_of_study, Innate immune system, medicine.diagnostic_test, biology, business.industry, SARS-CoV-2, COVID-19, Thrombosis, Hematology, medicine.disease, Immunity, Innate, Pneumonia, medicine.anatomical_structure, Bronchoalveolar lavage, Immunology, Host-Pathogen Interactions, biology.protein, Original Articals, business, monocytes

الوصف: Journal of thrombosis and haemostasis : JTH 19(2), 574-581 (2021). doi:10.1111/jth.15179
Published by Wiley-Blackwell, Oxford

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::50847fba788e6dcbf489faea0414480aTest