Molecular consequences of SARS-CoV-2 liver tropism

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Abstract

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae ¹. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated ^{2,
3}. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.

Abstract

Wanner et al. demonstrate SARS-CoV-2 liver tropism and identify transcriptional and proteomic profiles of SARS-CoV-2 liver samples that show similarities to previously characterized hepatotropic viruses.

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Most cited references 48

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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STAR: ultrafast universal RNA-seq aligner.

Alexander Dobin, Carrie A. Davis, Felix Schlesinger … (2013)

Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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Author and article information

Contributors

Victor G. Puelles:

ORCID: http://orcid.org/0000-0002-7735-5462

v.puelles@uke.de

Tobias B. Huber:

ORCID: http://orcid.org/0000-0001-7175-5062

t.huber@uke.de

Journal

Journal ID (nlm-ta): Nat Metab

Journal ID (iso-abbrev): Nat Metab

Title: Nature Metabolism

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2522-5812

Publication date (Electronic): 28 March 2022

Publication date PMC-release: 28 March 2022

Publication date (Print): 2022

Volume: 4

Issue: 3

Pages: 310-319

Affiliations

[1 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, III. Department of Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[2 ]GRID grid.7708.8, ISNI 0000 0000 9428 7911, Institute of Medical Bioinformatics and Systems Medicine, , Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, ; Freiburg, Germany

[3 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Institute for Computational Biomedicine, Faculty of Medicine, , Heidelberg University and Heidelberg University Hospital, BioQuant, ; Heidelberg, Germany

[4 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Legal Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[5 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Medical Microbiology, Virology and Hygiene, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[6 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Pathology, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[7 ]GRID grid.418481.0, ISNI 0000 0001 0665 103X, Leibniz Institute for Experimental Virology, ; Hamburg, Germany

[8 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Cardiology, , University Heart and Vascular Centre Hamburg, University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[9 ]GRID grid.452396.f, ISNI 0000 0004 5937 5237, DZHK (German Centre for Cardiovascular Research), , Partner Site Hamburg/Kiel/Lübeck, ; Hamburg, Germany

[10 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Intensive Care Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[11 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, I. Department of Medicine, , University Medical Hospital Hamburg-Eppendorf, ; Hamburg, Germany

[12 ]GRID grid.452463.2, German Center for Infection Research, , Hamburg-Lübeck-Borstel-Riems, ; Hamburg, Germany

[13 ]GRID grid.240684.c, ISNI 0000 0001 0705 3621, Department of Medicine, , Rush University Medical Center, ; Chicago, IL USA

[14 ]German Cancer Consortium and German Cancer Research Center, Partner Site Freiburg, Freiburg, Germany

[15 ]GRID grid.214458.e, ISNI 0000000086837370, Division of Cardiology, Department of Internal Medicine, , University of Michigan, ; Ann Arbor, MI USA

Author information

Geoffroy Andrieux http://orcid.org/0000-0002-5389-9481

Pau Badia-i-Mompel http://orcid.org/0000-0002-1004-3923

Susanne Pfefferle http://orcid.org/0000-0001-7489-6557

Christian Schmidt-Lauber http://orcid.org/0000-0002-7864-0361

Jan Czogalla http://orcid.org/0000-0003-1888-3369

Fabian Braun http://orcid.org/0000-0002-4742-050X

Marc Lütgehetmann http://orcid.org/0000-0002-9468-7944

Shun Lu http://orcid.org/0000-0003-4501-2008

Thomas Günther http://orcid.org/0000-0001-9650-0218

Adam Grundhoff http://orcid.org/0000-0003-0940-7045

Hanna Bräuninger http://orcid.org/0000-0002-4370-9509

Diana Lindner http://orcid.org/0000-0001-5477-769X

Fabian Haas http://orcid.org/0000-0001-5440-1035

Marylyn M. Addo http://orcid.org/0000-0003-2836-9224

Samuel Huber http://orcid.org/0000-0001-9325-8227

Julio Saez-Rodriguez http://orcid.org/0000-0002-8552-8976

Salim S. Hayek http://orcid.org/0000-0003-0180-349X

Pietro Scaturro http://orcid.org/0000-0001-9098-3087

Victor G. Puelles http://orcid.org/0000-0002-7735-5462

Tobias B. Huber http://orcid.org/0000-0001-7175-5062

Article

Publisher ID: 552

DOI: 10.1038/s42255-022-00552-6

PMC ID: 8964418

PubMed ID: 35347318

SO-VID: 55201399-c19e-4bcb-b22e-f631f9fd7155

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 November 2021

Date accepted : 14 February 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);

Award ID: CRC/1192

Award ID: CRC/841

Award ID: CRC/1453 Project ID 431984000 - S1

Award ID: TRR167 (Z1)

Award ID: CRC/850

Award ID: CRC/1160

Award ID: CRC1479

Award ID: SC 314/1-1

Award ID: CRC/1192

Award ID: SC 314/1-1

Award ID: HU 1016/8-2

Award ID: HU 1016/11-1

Award ID: HU 1016/12-1

Award Recipient : Nicola Wanner Samuel Huber Ansgar W. Lohse Melanie Boerries Pietro Scaturro Victor G. Puelles

Funded by: FundRef https://doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research);

Award ID: DEFEAT PANDEMIcs

Award ID: MIRACUM Consortia FKZ 01ZZ1801B

Award ID: DEFEAT PANDEMIcs

Award ID: eMed Consortia Fibromap

Award ID: STOP-FSGS- 01GM1901C

Award ID: DEFEAT PANDEMIcs

Award Recipient : Susanne Pfefferle Marc Lütgehetmann Nicole Fischer Samuel Huber Benjamin Ondruschka Melanie Boerries Martin Aepfelbacher Victor G. Puelles Tobias B. Huber

Funded by: FundRef https://doi.org/10.13039/100009139, Deutsches Zentrum für Infektionsforschung (German Center for Infection Research);

Award ID: TTU 01.921

Award ID: TTU 01.901

Award Recipient : Martin Aepfelbacher

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Keywords: sars-cov-2,liver,metabolism

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Keywords: sars-cov-2, liver, metabolism

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Molecular consequences of SARS-CoV-2 liver tropism

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Novel Coronavirus Disease COVID-19

Most cited references 48

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

STAR: ultrafast universal RNA-seq aligner.

Clinical Characteristics of Coronavirus Disease 2019 in China

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Cited by 63

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