SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis

Wendisch, Daniel; Dietrich, Oliver; Mari, Tommaso; Stillfried, Saskia von; Ibarra, Ignacio L.; Mittermaier, Mirja; Mache, Christin; Chua, Robert Lorenz; Knoll, Rainer; Timm, Sara; Brumhard, Sophia; Krammer, Tobias; Zauber, Henrik; Hiller, Anna Luisa; Pascual-Reguant, Anna; Mothes, Ronja; Schulze, Jessica; Leipold, Alexander; Djudjaj, Sonja; Erhard, Florian; Geffers, Robert; Pott, Fabian; Kazmierski, Julia; Radke, Josefine; Pergantis, Panagiotis; Baßler, Kevin; Conrad, C.; Aschenbrenner, Anna C.; Sawitzki, Birgit; Landthaler, Markus; Wyler, Emanuel; Horst, David; Hippenstiel, Stefan; Hocke, Andreas C.; Heppner, Frank L.; Uhrig, Alexander; García, Carmen; Machleidt, Felix; Herold, Susanne; Elezkurtaj, Sefer; Thibeault, Charlotte; Witzenrath, Martin; Cochain, Clément; Suttorp, Norbert; Drosten, Christian; Goffinet, Christine; Kurth, Florian; Schultze, Joachim L.; Radbruch, Helena; Ochs, Matthias; Eils, Roland; Müller-Redetzky, Holger; Hauser, Anja E.; Luecken, Malte D.; Theis, Fabian J.; Conrad, Christian; Wolff, Thorsten; Boor, Peter; Selbach, Matthias; Saliba, Antoine‐Emmanuel; Sander, Leif Erik

doi:10.1016/j.cell.2021.11.033

Cited by 367 publications

(399 citation statements)

References 137 publications

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“…Recently, similarities were found between macrophage populations in COVID-19 and idiopathic pulmonary fibrosis. Moreover, exposure of human monocytes to SARS-CoV-2 was shown to induce a profibrotic phenotype in vitro suggesting a role of pro-fibrotic macrophages in the development of fibroproliferative acute respiratory distress syndrome in COVID-19 [21].…”

Section: Introductionmentioning

confidence: 98%

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19

Kamp

Ackermann

Stark

et al. 2022

IJMS

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(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3–3.75) and 14 (12.5–14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.

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Section: Introductionmentioning

confidence: 98%

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19

Kamp

Ackermann

Stark

et al. 2022

IJMS

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“…In SARS-CoV-2 RNA-positive cells as compared to SARS-CoV-2 RNA-negative cells of the identical cultures, among others, CD163 reads tended to be slightly more abundant. Expression of the hemoglobin-haptoglobin scavenger receptor CD163 has been associated with regulation of inflammation (Kowal et al 2011) and has interestingly been linked to immunological changes in monocytes and monocyte-derived macrophages from SARS-CoV-2-infected individuals (Gómez-Rial et al 2020; Trombetta et al 2021; Wendisch et al 2021). Looking specifically at the CD163 HIGH monocyte population, we found that it displayed high expression levels of genes with profibrotic functions, in line with, including VCAN , LGMN , MERTK , TFGB1 , MRC1 , TGFBI and MMP9 and enhanced expression of cytokines including CCL2 , CXCL8 or IL1B and the cytokine receptor CCR5 ( Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…Peripheral immune cells are major contributors to human cellular responses upon infection. Given the recruitment of blood mononuclear cells to the lung compartment (Delorey et al 2021; Bost et al 2020; Wendisch et al 2021), and the reported presence of viral RNA detectable in the peripheral blood of up to 10% severely ill patients (Prebensen et al 2021; Andersson et al 2020), direct contact of PBMCs with SARS-CoV-2 virions is a likely scenario.…”

Section: Introductionmentioning

confidence: 99%

Non-productive exposure of PBMCs to SARS-CoV-2 induces cell-intrinsic innate immunity responses

Kazmierski

Friedmann

Postmus

et al. 2022

Preprint

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Cell-intrinsic responses mounted in vivo in PBMCs during mild and severe COVID-19 differ quantitatively and qualitatively. Whether they are triggered by signals emitted by productively infected cells of the respiratory tract or are, at least partially, resulting from physical interaction with virus particles, remains unclear. Here, we analyzed susceptibility and expression profiles of PBMCs from healthy donors upon ex vivo exposure to SARS-CoV and SARS-CoV-2. In line with the absence of detectable ACE2 receptor expression, human PBMCs were refractory to productive infection. Bulk and single cell RNA-sequencing revealed JAK/STAT-dependent induction of interferon-stimulated genes, but not pro-inflammatory cytokines. This SARS-CoV-2-specific response was most pronounced in monocytes. SARS-CoV-2-RNA-positive monocytes displayed a lower ISG signature as compared to bystander cells of the identical culture. This suggests a preferential invasion of cells with a low ISG base-line profile or delivery of a SARS-CoV-2-specific sensing antagonist upon efficient particle internalization. Together, non-productive physical interaction of PBMCs with SARS-CoV-2- but not SARS-CoV particles stimulates JAK/STAT-dependent, monocyte-accentuated innate immune responses that resemble those detected in vivo in patients with mild COVID-19.

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“…In COVID-19, the activation of such an immune response could be initiated by a signal of a preceding or an ongoing infection transported from the upper respiratory system or from other regions of the lung, perhaps, from only focally infected groups of cells. Activated mobile cells, like monocyte-derived macrophages, or virus material, such as RNA, which are regularly found in the lung of COVID-19 patients [ 14 , 33 ], could be initiators of the local (defense) response of the lung [ 34 – 36 ]. The results presented here suggest that progression of lung epithelial damage in fatal cases is independent of the presence and replication of the virus, supporting the hypothesis of a significant role of host response in the pathogenesis of lethal COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural examination of lung “cryobiopsies” from a series of fatal COVID-19 cases hardly revealed infected cells

et al. 2022

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Ultrastructural analysis of autopsy samples from COVID-19 patients usually suffers from significant structural impairment possibly caused by the rather long latency between death of the patient and an appropriate sample fixation. To improve structural preservation of the tissue, we obtained samples from ventilated patients using a trans-bronchial “cryobiopsy” within 30 min after their death and fixed them immediately for electron microscopy. Samples of six COVID-19 patients with a documented histopathology were systematically investigated by thin section electron microscopy. The different samples and areas inspected revealed the ultrastructural correlates of the different phases of diffuse alveolar damage, including detachment of the alveolar epithelium, hyperplasia of type 2 cells, exudates, and accumulation of extracellular material, such as the hyaline membranes and fibrin. Macrophages and neutrophilic granulocytes were regularly detected. Structural integrity of endothelium was intact in regions where the alveolar epithelium was already detached. Aggregates of erythrocytes, leukocytes with fibrin, and thrombocytes were not observed. Coronavirus particles were only found in and around very few cells in one of the six patient samples. The type and origin of these cells could not be assessed although the overall structural preservation of the samples allowed the identification of pulmonary cell types. Hence, the observed alveolar damage is not associated with virus presence or structural impairment due to ongoing replication at later stages of the disease in fatal cases, which implies that the lung damage in these patients is at least propagated by alternative mechanisms, perhaps, an inappropriate immune or stress response.

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SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis

Cited by 367 publications

References 137 publications

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19

Non-productive exposure of PBMCs to SARS-CoV-2 induces cell-intrinsic innate immunity responses

Ultrastructural examination of lung “cryobiopsies” from a series of fatal COVID-19 cases hardly revealed infected cells

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