Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart

Cardiovascular research

2021 Oct 14

Bräuninger, H;Stoffers, B;Fitzek, ADE;Meißner, K;Aleshcheva, G;Schweizer, M;Weimann, J;Rotter, B;Warnke, S;Edler, C;Braun, F;Roedl, K;Scherschel, K;Escher, F;Kluge, S;Huber, TB;Ondruschka, B;Schultheiss, HP;Kirchhof, P;Blankenberg, S;Püschel, K;Westermann, D;Lindner, D;
PMID: 34647998 | DOI: 10.1093/cvr/cvab322

Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19.In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). MACE-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset "Heart Cell Atlas" and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis.MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value <0.05 (e.g. up: IFI44L, IFT3, TRIM25; down: NPPB, MB, MYPN). The upregulated DEGs were linked to interferon pathways and originate predominantly from endothelial cells. In contrast, the downregulated DEGs originate predominately from cardiomyocytes. Immunofluorescent staining showed viral protein in cells positive for the endothelial marker ICAM1 but rarely in cardiomyocytes. The GO term analysis revealed that downregulated GO terms were linked to cardiomyocyte structure, whereas upregulated GO terms were linked to anti-virus immune response.This study reveals, that cardiac infection induced transcriptomic alterations mainly linked to immune response and destruction of cardiomyocytes. While endothelial cells are primarily targeted by the virus, we suggest cardiomyocyte-destruction by paracrine effects. Increased pro-inflammatory gene expression was detected in SARS-CoV-2-infected cardiac tissue but no increased SARS-CoV-2 associated immune cell infiltration was observed.Cardiac injury can be documented in COVID-19, regardless the direct cardiac virus infection and is known to be associated with outcome. However, the direct virus infection of the myocardium leads to transcriptomic alterations and might therefore additionally contribute to pathophysiological processes in COVID-19. Therefore, consequences of cardiac virus infection need to be investigated in future studies, since they might also contribute to long-term effects in case of survival.

Successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19

Clinical journal of gastroenterology

2021 Apr 11

Murota, A;Yoshi, S;Okuda, R;Oowada, S;Yamakawa, T;Kazama, T;Hirayama, D;Ishigami, K;Yamano, HO;Narimatu, E;Sugita, S;Hasegawa, T;Nakase, H;
PMID: 33840076 | DOI: 10.1007/s12328-021-01402-w

The coronavirus disease-2019 (COVID-19) has rapidly become a pandemic, resulting in a global suspension of non-emergency medical procedures such as screening endoscopic examinations. There have been several reports of COVID-19 patients presenting with gastrointestinal symptoms such as diarrhea and vomiting. In this report, we present a case of successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19. The case was under mechanical ventilation with extracorporeal membrane oxygenation (ECMO), and the airway was on a closed circuit. This indicates that COVID-19 is associated with not only lung injury but also intestinal damage, and that proper protective protocols are essential in guaranteeing the best outcomes for patients and clinical professionals during this pandemic.

Rapid endotheliitis and vascular damage characterize SARS-CoV-2 infection in a human lung-on-chip model

EMBO reports

2021 Apr 28

Thacker, VV;Sharma, K;Dhar, N;Mancini, GF;Sordet-Dessimoz, J;McKinney, JD;
PMID: 33908688 | DOI: 10.15252/embr.202152744

Severe cases of SARS-CoV-2 infection are characterized by hypercoagulopathies and systemic endotheliitis of the lung microvasculature. The dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of an immune cell-mediated cytokine storm remain unknown. Using a vascularized lung-on-chip model, we find that infection of alveolar epithelial cells leads to limited apical release of virions, consistent with reports of monoculture infection. However, viral RNA and proteins are rapidly detected in underlying endothelial cells, which are themselves refractory to apical infection in monocultures. Although endothelial infection is unproductive, it leads to the formation of cell clusters with low CD31 expression, a progressive loss of barrier integrity and a pro-coagulatory microenvironment. Viral RNA persists in individual cells generating an inflammatory response, which is transient in epithelial cells but persistent in endothelial cells and typified by IL-6 secretion even in the absence of immune cells. Inhibition of IL-6 signalling with tocilizumab reduces but does not prevent loss of barrier integrity. SARS-CoV-2-mediated endothelial cell damage thus occurs independently of cytokine storm.

Immune imprinting, breadth of variant recognition and germinal center response in human SARS-CoV-2 infection and vaccination

Cell

2022 Jan 01

Röltgen, K;Nielsen, S;Silva, O;Younes, S;Maxim Zaslavsky, ;Costales, C;Yang, F;Wirz, O;Solis, D;Hoh, R;Wang, A;Arunachalam, P;Colburg, D;Zhao, S;Haraguchi, E;Lee, A;Shah, M;Manohar, M;Chang, I;Gao, F;Mallajosyula, V;Li, C;Liu, J;Shoura, M;Sindher, S;Parsons, E;Dashdorj, N;Dashdorj, N;Monroe, R;Serrano, G;Beach, T;Chinthrajah, R;Charville, G;Wilbur, J;Wohlstadter, J;Davis, M;Pulendran, B;Troxell, M;Sigal, G;Natkunam, Y;Pinsky, B;Nadeau, K;Boyd, S;
| DOI: 10.1016/j.cell.2022.01.018

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including 3rd dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is less after infection compared to all vaccines evaluated, but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks post-vaccination in some cases. SARS-CoV-2 antibody specificity, breadth and maturation are affected by imprinting from exposure history, and distinct histological and antigenic contexts in infection compared to vaccination.

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

Cell

2021 Nov 01

Wendisch, D;Dietrich, O;Mari, T;von Stillfried, S;Ibarra, I;Mittermaier, M;Mache, C;Chua, R;Knoll, R;Timm, S;Brumhard, S;Krammer, T;Zauber, H;Hiller, A;Pascual-Reguant, A;Mothes, R;Bülow, R;Schulze, J;Leipold, A;Djudjaj, S;Erhard, F;Geffers, R;Pott, F;Kazmierski, J;Radke, J;Pergantis, P;Baßler, K;Conrad, C;Aschenbrenner, A;Sawitzki, B;Landthaler, M;Wyler, E;Horst, D;Hippenstiel, S;Hocke, A;Heppner, F;Uhrig, A;Garcia, C;Machleidt, F;Herold, S;Elezkurtaj, S;Thibeault, C;Witzenrath, M;Cochain, C;Suttorp, N;Drosten, C;Goffinet, C;Kurth, F;Schultze, J;Radbruch, H;Ochs, M;Eils, R;Müller-Redetzky, H;Hauser, A;Luecken, M;Theis, F;Conrad, C;Wolff, T;Boor, P;Selbach, M;Saliba, A;Sander, L;
| DOI: 10.1016/j.cell.2021.11.033

COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

Peripheral and lung resident memory T cell responses against SARS-CoV-2

Nature communications

2021 May 21

Grau-Expósito, J;Sánchez-Gaona, N;Massana, N;Suppi, M;Astorga-Gamaza, A;Perea, D;Rosado, J;Falcó, A;Kirkegaard, C;Torrella, A;Planas, B;Navarro, J;Suanzes, P;Álvarez-Sierra, D;Ayora, A;Sansano, I;Esperalba, J;Andrés, C;Antón, A;Ramón Y Cajal, S;Almirante, B;Pujol-Borrell, R;Falcó, V;Burgos, J;Buzón, MJ;Genescà, M;
PMID: 34021148 | DOI: 10.1038/s41467-021-23333-3

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.

Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction

Research square

2021 Nov 24

Gajewski, T;Rouhani, S;Trujillo, J;Pyzer, A;Yu, J;Fessler, J;Cabanov, A;Higgs, E;Cron, K;Zha, Y;Lu, Y;Bloodworth, J;Abasiyanik, M;Okrah, S;Flood, B;Hatogai, K;Leung, M;Pezeshk, A;Kozloff, L;Reschke, R;Strohbehn, G;Chervin, CS;Kumar, M;Schrantz, S;Madariaga, ML;Beavis, K;Yeo, KT;Sweis, R;Segal, J;Tay, S;Izumchenko, E;Mueller, J;Chen, L;
PMID: 34845442 | DOI: 10.21203/rs.3.rs-1083825/v1

The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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