Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

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Summary

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

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Highlights

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SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
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Strong chemokine expression is consistent across in vitro, ex vivo, and in vivo models
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Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19

Abstract

In comparison to other respiratory viruses, SARS-CoV-2 infection drives a lower antiviral transcriptional response that is marked by low IFN-I and IFN-III levels and elevated chemokine expression, which could explain the pro-inflammatory disease state associated with COVID-19.

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Most cited references 15

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A penalized matrix decomposition, with applications to sparse principal components and canonical correlation analysis.

Daniela M. Witten, Robert Tibshirani, Trevor J. Hastie (2009)

We present a penalized matrix decomposition (PMD), a new framework for computing a rank-K approximation for a matrix. We approximate the matrix X as circumflexX = sigma(k=1)(K) d(k)u(k)v(k)(T), where d(k), u(k), and v(k) minimize the squared Frobenius norm of X - circumflexX, subject to penalties on u(k) and v(k). This results in a regularized version of the singular value decomposition. Of particular interest is the use of L(1)-penalties on u(k) and v(k), which yields a decomposition of X using sparse vectors. We show that when the PMD is applied using an L(1)-penalty on v(k) but not on u(k), a method for sparse principal components results. In fact, this yields an efficient algorithm for the "SCoTLASS" proposal (Jolliffe and others 2003) for obtaining sparse principal components. This method is demonstrated on a publicly available gene expression data set. We also establish connections between the SCoTLASS method for sparse principal component analysis and the method of Zou and others (2006). In addition, we show that when the PMD is applied to a cross-products matrix, it results in a method for penalized canonical correlation analysis (CCA). We apply this penalized CCA method to simulated data and to a genomic data set consisting of gene expression and DNA copy number measurements on the same set of samples.

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The lung is a site of platelet biogenesis and a reservoir for hematopoietic progenitors

Emma Lefrancais, Guadalupe Ortiz-Muñoz, Axelle Caudrillier … (2017)

Platelets are critical for hemostasis, thrombosis, and inflammatory responses 1,2 , yet the events leading to mature platelet production remain incompletely understood 3 . The bone marrow (BM) is proposed to be a major site of platelet production although indirect evidence points towards a potential pulmonary contribution to platelet biogenesis 4-7 . By directly imaging the lung microcirculation in mice 8 , we discovered that a large number of megakaryocytes (MKs) circulate through the lungs where they dynamically release platelets. MKs releasing platelets in the lung are of extrapulmonary origin, such as the BM, where we observed large MKs migrating out of the BM space. The lung contribution to platelet biogenesis is substantial with approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature MKs along with hematopoietic progenitors that reside in the extravascular spaces of the lung. Under conditions of thrombocytopenia and relative stem cell deficiency in the BM 9 , these progenitors can migrate out of the lung, repopulate the BM, completely reconstitute blood platelet counts, and contribute to multiple hematopoietic lineages. These results position the lung as a primary site of terminal platelet production and an organ with considerable hematopoietic potential.

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Triggering the interferon antiviral response through an IKK-related pathway.

Sonia Sharma, Benjamin tenOever, Nathalie Grandvaux … (2003)

Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor kappaB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.

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Author and article information

Contributors

Robert E. Schwartz

Jean K. Lim

Randy A. Albrecht

Benjamin R. tenOever

Journal

Journal ID (nlm-ta): Cell

Journal ID (iso-abbrev): Cell

Title: Cell

Publisher: Elsevier Inc.

ISSN (Print): 0092-8674

ISSN (Electronic): 1097-4172

Publication date PMC-release: 15 May 2020

Publication date (Electronic): 15 May 2020

Affiliations

[1 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

[2 ]Virus Engineering Center for Therapeutics and Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA

[3 ]Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

[4 ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

[5 ]Divison of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

[6 ]Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA

[7 ]Chan Zuckerberg Biohub, San Francisco, CA, USA

[8 ]Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

Author notes

[∗ ]Corresponding author res2025@ 123456med.cornell.edu

[∗∗ ]Corresponding author jean.lim@ 123456mssm.edu

[∗∗∗ ]Corresponding author randy.albrecht@ 123456mssm.edu

[∗∗∗∗ ]Corresponding author benjamin.tenoever@ 123456mssm.edu

[9]

These authors contributed equally

[10]

Lead Contact

Article

Publisher ID: S0092-8674(20)30489-X

DOI: 10.1016/j.cell.2020.04.026

PMC ID: 7227586

PubMed ID: 32416070

SO-VID: c6bf44c5-e569-4af8-bdc7-3d5a5d787fa3

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 1 April 2020

Date revision received : 9 April 2020

Date accepted : 15 April 2020

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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

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Novel Coronavirus Disease COVID-19

Most cited references 15

A penalized matrix decomposition, with applications to sparse principal components and canonical correlation analysis.

The lung is a site of platelet biogenesis and a reservoir for hematopoietic progenitors

Triggering the interferon antiviral response through an IKK-related pathway.

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Cited by 2,284