Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Lok-Yin Roy Wong; Jian Zheng; Kevin Wilhelmsen; Kun Li; Miguel E. Ortiz; Nicholas J. Schnicker; Andrew Thurman; Alejandro A. Pezzulo; Peter J. Szachowicz; Pengfei Li; Ruangang Pan; Klaus Klumpp; Fred Aswad; Justin Rebo; Shuh Narumiya; Makoto Murakami; Sonia Zuniga; Isabel Sola; Luis Enjuanes; David K. Meyerholz; Kristen Fortney; Paul B. Jr Jr McCray; Stanley Perlman

doi:10.1038/s41586-022-04630-3

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Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Journal article

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Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Lok-Yin Roy Wong, Jian Zheng, Kevin Wilhelmsen, Kun Li, Miguel E. Ortiz, Nicholas J. Schnicker, Andrew Thurman, Alejandro A. Pezzulo, Peter J. Szachowicz, Pengfei Li, …

Nature (London), Vol.605(7908), pp.146-151

03/21/2022

DOI: 10.1038/s41586-022-04630-3

PMCID: PMC9783543

PMID: 35314834

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Abstract

Coronavirus disease 2019 (COVID-19) is especially severe in aged populations(1). Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility(2). The emergence ofthese variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a newtherapeutic drug in infected aged animals. Many ofthe alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 ofthe spike protein) also arise in humans in variants of concern(2). Their appearance during mouse adaptation indicatesthat immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D-2 (PGD(2))) and a phospholipase (phospholipase A2 group 2D (PLA(2)G2D)) contributed to poor outcomes in aged mice(3,)(4). mRNA expression of PLA(2)G2D and prostaglandin D-2 receptor (PTGDR), and production of PGD(2) also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA(2)G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one ofthe first interventions in SARS-CoV-2-infected animalsthat specifically protects aged animals, suggesting that the PLA(2)G2D-PGD(2)/PTGDR pathway is a useful target for therapeutic interventions.

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Title: Subtitle: Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19
Creators: Lok-Yin Roy Wong - University of Iowa
Jian Zheng - University of Iowa
Kevin Wilhelmsen - BioAge (Italy)
Kun Li - University of Iowa
Miguel E. Ortiz - University of Iowa
Nicholas J. Schnicker - University of Iowa
Andrew Thurman - University of Iowa
Alejandro A. Pezzulo - University of Iowa
Peter J. Szachowicz - University of Iowa
Pengfei Li - Univ Iowa, Dept Microbiol & Immunol, Iowa City, IA 52242 USA
Ruangang Pan - University of Iowa
Klaus Klumpp - BioAge (Italy)
Fred Aswad - BioAge (Italy)
Justin Rebo - BioAge (Italy)
Shuh Narumiya - Kyoto University
Makoto Murakami - The University of Tokyo
Sonia Zuniga - Universidad Autónoma de Madrid
Isabel Sola - Universidad Autónoma de Madrid
Luis Enjuanes - Universidad Autónoma de Madrid
David K. Meyerholz - University of Iowa
Kristen Fortney - BioAge (Italy)
Paul B. Jr Jr McCray - Univ Iowa, Dept Microbiol & Immunol, Iowa City, IA 52242 USA
Stanley Perlman - University of Iowa
Resource Type: Journal article
Publication Details: Nature (London), Vol.605(7908), pp.146-151
DOI: 10.1038/s41586-022-04630-3
PMID: 35314834
PMCID: PMC9783543
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Publisher: NATURE PORTFOLIO
Number of pages: 21
Grant note: P01 AI060699; R01 AI129269 / National Institutes of Health USA (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation BIOAGE Labs P30 DK-54759 / Center for Gene Therapy for Cystic Fibrosis (NIH) Roy J. Carver Charitable Trust T32 AI007511 / Mechanism of Parasitism Training Grant
Language: English
Date published: 03/21/2022
Academic Unit: Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics); Internal Medicine
Record Identifier: 9984297439402771

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