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  1. Article ; Online: Case Report: Gene expression profiling of COVID-19 vaccination-related lymphadenopathies reveals evidence of a dominantly extrafollicular immune response.

    Menter, Thomas / Zinner, Carl P / Berger, Christoph T / Went, Philip / Tzankov, Alexandar

    Frontiers in immunology

    2023  Volume 14, Page(s) 1285168

    Abstract: mRNA-based vaccines against SARS-CoV-2 have been proven to be very efficient in preventing severe COVID-19. Temporary lymphadenopathy (LA) has been observed as a common adverse event following immunization. Here we describe a case series of three female ... ...

    Abstract mRNA-based vaccines against SARS-CoV-2 have been proven to be very efficient in preventing severe COVID-19. Temporary lymphadenopathy (LA) has been observed as a common adverse event following immunization. Here we describe a case series of three female patients with prominent local to generalized LA after SARS-CoV-2 mRNA-1273 vaccination, which led to lymph node biopsy due to the suspicion of lymphoma or metastasis. All three patients morphologically showed similar patterns of follicular hyperplasia and especially extrafollicular blast activation. Two of the three patients only had short-lasting humoral immune responses to the vaccination. Gene expression profiling (GEP) using the HTG
    MeSH term(s) Female ; Humans ; 2019-nCoV Vaccine mRNA-1273 ; COVID-19 ; COVID-19 Vaccines/adverse effects ; Gene Expression Profiling ; Hyperplasia ; Immunologic Memory ; Lymphadenopathy/etiology ; SARS-CoV-2 ; Vaccination/adverse effects
    Chemical Substances 2019-nCoV Vaccine mRNA-1273 (EPK39PL4R4) ; COVID-19 Vaccines
    Language English
    Publishing date 2023-11-14
    Publishing country Switzerland
    Document type Case Reports ; Research Support, Non-U.S. Gov't ; Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1285168
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Differential Gene Expression of SARS-CoV-2 Positive Bronchoalveolar Lavages: A Case Series.

    Haslbauer, Jasmin D / Savic Prince, Spasenija / Stalder, Anna K / Matter, Matthias S / Zinner, Carl P / Jahn, Kathleen / Obermann, Ellen / Hanke, Jasmin / Leuzinger, Karoline / Hirsch, Hans H / Tzankov, Alexandar

    Pathobiology : journal of immunopathology, molecular and cellular biology

    2023  Volume 91, Issue 2, Page(s) 158–168

    Abstract: Background: Transcriptomic data on bronchoalveolar lavage (BAL) from COVID-19 patients are currently scarce.: Objectives: This case series seeks to characterize the intra-alveolar immunopathology of COVID-19.: Method: BALs were performed on 14 ... ...

    Abstract Background: Transcriptomic data on bronchoalveolar lavage (BAL) from COVID-19 patients are currently scarce.
    Objectives: This case series seeks to characterize the intra-alveolar immunopathology of COVID-19.
    Method: BALs were performed on 14 patients (5 COVID-19, of which 3 mild and 2 largely asymptomatic, 9 controls). Controls included asthma (n = 1), unremarkable BALs (n = 3), infections with respiratory syncytial virus (n = 1), influenza B (n = 1), and infections with other coronaviruses (n = 3). SARS-CoV-2 RNA load was measured by quantitative nucleic acid testing, while the detection of other pathogens was performed by immunofluorescence or multiplex NAT.
    Results: Gene expression profiling showed 71 significantly downregulated and 5 upregulated transcripts in SARS-CoV-2-positive lavages versus controls. Downregulated transcripts included genes involved in macrophage development, polarization, and crosstalk (LGALS3, MARCO, ERG2, BTK, RAC1, CD83), and genes involved in chemokine signaling and immunometabolism (NUPR1, CEBPB, CEBPA, PECAM1, CCL18, PPARG, ALOX5, ALOX5AP). Upregulated transcripts featured genes involved in NK-T cell signaling (GZMA, GZMH, GNLY, PRF1, CD3G). Patients with mild COVID-19 showed a significant upregulation of genes involved in blood mononuclear cell/leukocyte function (G0S2, ANXA6, FCGR2B, ADORA3), coagulation (von Willebrand factor [VWF]), interferon response (IFRD1, IL12RB2), and a zinc metalloprotease elevated in asthma (CPA3) compared to asymptomatic cases. In-silico comparison of the 5 COVID-19 BAL cases to a published cohort of lethal COVID-19 showed a significant upregulation of "antigen processing and presentation" and "lysosome" pathways in lethal cases.
    Conclusions: These data underscore the heterogeneity of immune response in COVID-19. Further studies with a larger dataset are required to gain a better understanding of the hallmarks of SARS-CoV-2 immunological response.
    MeSH term(s) Humans ; COVID-19/genetics ; SARS-CoV-2 ; RNA, Viral ; Bronchoalveolar Lavage ; Asthma ; Transcriptome
    Chemical Substances RNA, Viral
    Language English
    Publishing date 2023-07-25
    Publishing country Switzerland
    Document type News
    ZDB-ID 1022703-9
    ISSN 1423-0291 ; 1015-2008
    ISSN (online) 1423-0291
    ISSN 1015-2008
    DOI 10.1159/000532057
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Emergence of consistent intra-individual locomotor patterns during zebrafish development.

    Fitzgerald, Jennifer A / Kirla, Krishna Tulasi / Zinner, Carl P / Vom Berg, Colette M

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 13647

    Abstract: The analysis of larval zebrafish locomotor behavior has emerged as a powerful indicator of perturbations in the nervous system and is used in many fields of research, including neuroscience, toxicology and drug discovery. The behavior of larval zebrafish ...

    Abstract The analysis of larval zebrafish locomotor behavior has emerged as a powerful indicator of perturbations in the nervous system and is used in many fields of research, including neuroscience, toxicology and drug discovery. The behavior of larval zebrafish however, is highly variable, resulting in the use of large numbers of animals and the inability to detect small effects. In this study, we analyzed whether individual locomotor behavior is stable over development and whether behavioral parameters correlate with physiological and morphological features, with the aim of better understanding the variability and predictability of larval locomotor behavior. Our results reveal that locomotor activity of an individual larva remains consistent throughout a given day and is predictable throughout larval development, especially during dark phases, under which larvae demonstrate light-searching behaviors and increased activity. The larvae's response to startle-stimuli was found to be unpredictable, with no correlation found between response strength and locomotor activity. Furthermore, locomotor activity was not associated with physiological or morphological features of a larva (resting heart rate, body length, size of the swim bladder). Overall, our findings highlight the areas of intra-individual consistency, which could be used to improve the sensitivity of assays using zebrafish locomotor activity as an endpoint.
    MeSH term(s) Acclimatization ; Animals ; Behavior, Animal/physiology ; Heart Rate/radiation effects ; Larva/growth & development ; Larva/physiology ; Larva/radiation effects ; Light ; Locomotion ; Photic Stimulation ; Zebrafish/growth & development ; Zebrafish/physiology
    Language English
    Publishing date 2019-09-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-49614-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19.

    Sahanic, Sabina / Hilbe, Richard / Dünser, Christina / Tymoszuk, Piotr / Löffler-Ragg, Judith / Rieder, Dietmar / Trajanoski, Zlatko / Krogsdam, Anne / Demetz, Egon / Yurchenko, Maria / Fischer, Christine / Schirmer, Michael / Theurl, Markus / Lener, Daniela / Hirsch, Jakob / Holfeld, Johannes / Gollmann-Tepeköylü, Can / Zinner, Carl P / Tzankov, Alexandar /
    Zhang, Shen-Ying / Casanova, Jean-Laurent / Posch, Wilfried / Wilflingseder, Doris / Weiss, Guenter / Tancevski, Ivan

    Heliyon

    2023  Volume 9, Issue 11, Page(s) e21893

    Abstract: Background: Toll-like receptors (TLRs) play a pivotal role in the immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exaggerated inflammatory response of innate immune cells, however, may drive morbidity and ... ...

    Abstract Background: Toll-like receptors (TLRs) play a pivotal role in the immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exaggerated inflammatory response of innate immune cells, however, may drive morbidity and death in Coronavirus disease 19 (COVID-19).
    Objective: We investigated the engagement of SARS-CoV-2 with TLR4 in order to better understand how to tackle hyperinflammation in COVID-19.
    Methods: We combined RNA-sequencing data of human lung tissue and of bronchoalveolar lavage fluid cells derived from COVID-19 patients with functional studies in human macrophages using SARS-CoV-2 spike proteins and viable SARS-CoV-2. Pharmacological inhibitors as well as gene editing with CRISPR/Cas9 were used to delineate the signalling pathways involved.
    Results: We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron).
    Conclusion: Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19.
    Take-home message: Our study combining human lung transcriptomics with functional studies in human macrophages clearly supports the design and development of TLR4 - directed therapeutics to mitigate hyperinflammation in severe COVID-19.
    Language English
    Publishing date 2023-11-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 2835763-2
    ISSN 2405-8440
    ISSN 2405-8440
    DOI 10.1016/j.heliyon.2023.e21893
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.

    Shekarian, Tala / Zinner, Carl P / Bartoszek, Ewelina M / Duchemin, Wandrille / Wachnowicz, Anna T / Hogan, Sabrina / Etter, Manina M / Flammer, Julia / Paganetti, Chiara / Martins, Tomas A / Schmassmann, Philip / Zanganeh, Steven / Le Goff, Francois / Muraro, Manuele G / Ritz, Marie-Françoise / Phillips, Darci / Bhate, Salil S / Barlow, Graham L / Nolan, Garry P /
    Schürch, Christian M / Hutter, Gregor

    Science advances

    2022  Volume 8, Issue 26, Page(s) eabn9440

    Abstract: A patient-tailored, ex vivo drug response platform for glioblastoma (GBM) would facilitate therapy planning, provide insights into treatment-induced mechanisms in the immune tumor microenvironment (iTME), and enable the discovery of biomarkers of ... ...

    Abstract A patient-tailored, ex vivo drug response platform for glioblastoma (GBM) would facilitate therapy planning, provide insights into treatment-induced mechanisms in the immune tumor microenvironment (iTME), and enable the discovery of biomarkers of response. We cultured regionally annotated GBM explants in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were treated with anti-CD47, anti-PD-1, or their combination, and analyzed by multiplexed microscopy [CO-Detection by indEXing (CODEX)], enabling the spatially resolved identification of >850,000 single cells, accompanied by explant secretome interrogation. Center and periphery explants differed in their cell type and soluble factor composition, and responses to immunotherapy. A subset of explants displayed increased interferon-γ levels, which correlated with shifts in immune cell composition within specified tissue compartments. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.
    Language English
    Publishing date 2022-07-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abn9440
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  6. Article ; Online: Morphologic and molecular analysis of liver injury after SARS-CoV-2 vaccination reveals distinct characteristics.

    Uzun, Sarp / Zinner, Carl P / Beenen, Amke C / Alborelli, Ilaria / Bartoszek, Ewelina M / Yeung, Jason / Calgua, Byron / Reinscheid, Matthias / Bronsert, Peter / Stalder, Anna K / Haslbauer, Jasmin D / Vosbeck, Juerg / Mazzucchelli, Luca / Hoffmann, Tobias / Terracciano, Luigi M / Hutter, Gregor / Manz, Michael / Panne, Isabelle / Boettler, Tobias /
    Hofmann, Maike / Bengsch, Bertram / Heim, Markus H / Bernsmeier, Christine / Jiang, Sizun / Tzankov, Alexandar / Terziroli Beretta-Piccoli, Benedetta / Matter, Matthias S

    Journal of hepatology

    2023  Volume 79, Issue 3, Page(s) 666–676

    Abstract: Background & aims: Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and ...

    Abstract Background & aims: Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and its relationship to AIH. Therefore, we compared VILI with AIH.
    Methods: Formalin-fixed and paraffin-embedded liver biopsy samples from patients with VILI (n = 6) and from patients with an initial diagnosis of AIH (n = 9) were included. Both cohorts were compared by histomorphological evaluation, whole-transcriptome and spatial transcriptome sequencing, multiplex immunofluorescence, and immune repertoire sequencing.
    Results: Histomorphology was similar in both cohorts but showed more pronounced centrilobular necrosis in VILI. Gene expression profiling showed that mitochondrial metabolism and oxidative stress-related pathways were more and interferon response pathways were less enriched in VILI. Multiplex analysis revealed that inflammation in VILI was dominated by CD8
    Conclusions: Our analyses support that SARS-CoV-2 VILI is related to AIH but also shows distinct differences from AIH in histomorphology, pathway activation, cellular immune infiltrates, and TCR usage. Therefore, VILI may be a separate entity, which is distinct from AIH and more closely related to drug-induced autoimmune-like hepatitis.
    Impact and implications: Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI). Our analysis shows that COVID-19 VILI shares some similarities with autoimmune hepatitis, but also has distinct differences such as increased activation of metabolic pathways, a more prominent CD8+ T cell infiltrate, and an oligoclonal T and B cell response. Our findings suggest that VILI is a distinct disease entity. Therefore, there is a good chance that many patients with COVID-19 VILI will recover completely and will not develop long-term autoimmune hepatitis.
    MeSH term(s) Humans ; COVID-19 Vaccines/adverse effects ; Hepatitis, Autoimmune ; SARS-CoV-2 ; Chemical and Drug Induced Liver Injury, Chronic ; COVID-19/prevention & control ; Liver/pathology ; Receptors, Antigen, T-Cell ; Vaccination
    Chemical Substances COVID-19 Vaccines ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-06-07
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 605953-3
    ISSN 1600-0641 ; 0168-8278
    ISSN (online) 1600-0641
    ISSN 0168-8278
    DOI 10.1016/j.jhep.2023.05.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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