Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

ABSTRACT Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understa...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xiang Liu, Ali Zaid, Joseph R. Freitas, Nigel A. McMillan, Suresh Mahalingam, Adam Taylor
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	coronavirus cytokines infectious clones lung infection respiratory viruses Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a2d1ee758a204008aba29455c8901d6d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a2d1ee758a204008aba29455c8901d6d
record_format	dspace
spelling	oai:doaj.org-article:a2d1ee758a204008aba29455c8901d6d2021-11-10T18:37:48ZInfectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice10.1128/mBio.00819-212150-7511https://doaj.org/article/a2d1ee758a204008aba29455c8901d6d2021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00819-21https://doaj.org/toc/2150-7511ABSTRACT Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development. IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit’s value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.Xiang LiuAli ZaidJoseph R. FreitasNigel A. McMillanSuresh MahalingamAdam TaylorAmerican Society for Microbiologyarticlecoronaviruscytokinesinfectious cloneslung infectionrespiratory virusesMicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	coronavirus cytokines infectious clones lung infection respiratory viruses Microbiology QR1-502
spellingShingle	coronavirus cytokines infectious clones lung infection respiratory viruses Microbiology QR1-502 Xiang Liu Ali Zaid Joseph R. Freitas Nigel A. McMillan Suresh Mahalingam Adam Taylor Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice
description	ABSTRACT Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development. IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit’s value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.
format	article
author	Xiang Liu Ali Zaid Joseph R. Freitas Nigel A. McMillan Suresh Mahalingam Adam Taylor
author_facet	Xiang Liu Ali Zaid Joseph R. Freitas Nigel A. McMillan Suresh Mahalingam Adam Taylor
author_sort	Xiang Liu
title	Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice
title_short	Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice
title_full	Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice
title_fullStr	Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice
title_full_unstemmed	Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice
title_sort	infectious clones produce sars-cov-2 that causes severe pulmonary disease in infected k18-human ace2 mice
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/a2d1ee758a204008aba29455c8901d6d
work_keys_str_mv	AT xiangliu infectiousclonesproducesarscov2thatcausesseverepulmonarydiseaseininfectedk18humanace2mice AT alizaid infectiousclonesproducesarscov2thatcausesseverepulmonarydiseaseininfectedk18humanace2mice AT josephrfreitas infectiousclonesproducesarscov2thatcausesseverepulmonarydiseaseininfectedk18humanace2mice AT nigelamcmillan infectiousclonesproducesarscov2thatcausesseverepulmonarydiseaseininfectedk18humanace2mice AT sureshmahalingam infectiousclonesproducesarscov2thatcausesseverepulmonarydiseaseininfectedk18humanace2mice AT adamtaylor infectiousclonesproducesarscov2thatcausesseverepulmonarydiseaseininfectedk18humanace2mice
_version_	1718439900858023936

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Ejemplares similares