tetano
Editor, Senior Moderator
Sci Transl Med
. 2022 Jul 7;eabo5070.
doi: 10.1126/scitranslmed.abo5070. Online ahead of print.
SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice
Kenneth H Dinnon 3rd[SUP] #[/SUP][SUP] 1 [/SUP], Sarah R Leist[SUP] #[/SUP][SUP] 2 [/SUP], Kenichi Okuda[SUP] #[/SUP][SUP] 3 [/SUP], Hong Dang[SUP] #[/SUP][SUP] 3 [/SUP], Ethan J Fritch[SUP] #[/SUP][SUP] 1 [/SUP], Kendra L Gully[SUP] 2 [/SUP], Gabriela De la Cruz[SUP] 4 [/SUP], Mia D Evangelista[SUP] 4 [/SUP], Takanori Asakura[SUP] 3 [/SUP], Rodney C Gilmore[SUP] 3 [/SUP], Padraig Hawkins[SUP] 3 [/SUP], Satoko Nakano[SUP] 3 [/SUP], Ande West[SUP] 2 [/SUP], Alexandra Schäfer[SUP] 2 [/SUP], Lisa E Gralinski[SUP] 2 [/SUP], Jamie L Everman[SUP] 5 [/SUP], Satria P Sajuthi[SUP] 5 [/SUP], Mark R Zweigart[SUP] 2 [/SUP], Stephanie Dong[SUP] 2 [/SUP], Jennifer McBride[SUP] 2 [/SUP], Michelle R Cooley[SUP] 2 [/SUP], Jesse B Hines[SUP] 6 [/SUP], Miriya K Love[SUP] 3 [/SUP], Steve D Groshong[SUP] 7 [/SUP], Alison VanSchoiack[SUP] 8 [/SUP], Stefan J Phelan[SUP] 8 [/SUP], Yan Liang[SUP] 8 [/SUP], Tyler Hether[SUP] 8 [/SUP], Michael Leon[SUP] 8 [/SUP], Ross E Zumwalt[SUP] 9 [/SUP], Lisa M Barton[SUP] 10 [/SUP], Eric J Duval[SUP] 10 [/SUP], Sanjay Mukhopadhyay[SUP] 11 [/SUP], Edana Stroberg[SUP] 10 [/SUP], Alain Borczuk[SUP] 12 [/SUP], Leigh B Thorne[SUP] 13 [/SUP], Muthu K Sakthivel[SUP] 14 [/SUP], Yueh Z Lee[SUP] 14 15 [/SUP], James S Hagood[SUP] 3 16 [/SUP], Jason R Mock[SUP] 3 17 [/SUP], Max A Seibold[SUP] 5 18 19 [/SUP], Wanda K O'Neal[SUP] #[/SUP][SUP] 3 [/SUP], Stephanie A Montgomery[SUP] #[/SUP][SUP] 4 13 [/SUP], Richard C Boucher[SUP] #[/SUP][SUP] 3 [/SUP], Ralph S Baric[SUP] #[/SUP][SUP] 1 2 20 [/SUP]
Affiliations
Abstract
A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
. 2022 Jul 7;eabo5070.
doi: 10.1126/scitranslmed.abo5070. Online ahead of print.
SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice
Kenneth H Dinnon 3rd[SUP] #[/SUP][SUP] 1 [/SUP], Sarah R Leist[SUP] #[/SUP][SUP] 2 [/SUP], Kenichi Okuda[SUP] #[/SUP][SUP] 3 [/SUP], Hong Dang[SUP] #[/SUP][SUP] 3 [/SUP], Ethan J Fritch[SUP] #[/SUP][SUP] 1 [/SUP], Kendra L Gully[SUP] 2 [/SUP], Gabriela De la Cruz[SUP] 4 [/SUP], Mia D Evangelista[SUP] 4 [/SUP], Takanori Asakura[SUP] 3 [/SUP], Rodney C Gilmore[SUP] 3 [/SUP], Padraig Hawkins[SUP] 3 [/SUP], Satoko Nakano[SUP] 3 [/SUP], Ande West[SUP] 2 [/SUP], Alexandra Schäfer[SUP] 2 [/SUP], Lisa E Gralinski[SUP] 2 [/SUP], Jamie L Everman[SUP] 5 [/SUP], Satria P Sajuthi[SUP] 5 [/SUP], Mark R Zweigart[SUP] 2 [/SUP], Stephanie Dong[SUP] 2 [/SUP], Jennifer McBride[SUP] 2 [/SUP], Michelle R Cooley[SUP] 2 [/SUP], Jesse B Hines[SUP] 6 [/SUP], Miriya K Love[SUP] 3 [/SUP], Steve D Groshong[SUP] 7 [/SUP], Alison VanSchoiack[SUP] 8 [/SUP], Stefan J Phelan[SUP] 8 [/SUP], Yan Liang[SUP] 8 [/SUP], Tyler Hether[SUP] 8 [/SUP], Michael Leon[SUP] 8 [/SUP], Ross E Zumwalt[SUP] 9 [/SUP], Lisa M Barton[SUP] 10 [/SUP], Eric J Duval[SUP] 10 [/SUP], Sanjay Mukhopadhyay[SUP] 11 [/SUP], Edana Stroberg[SUP] 10 [/SUP], Alain Borczuk[SUP] 12 [/SUP], Leigh B Thorne[SUP] 13 [/SUP], Muthu K Sakthivel[SUP] 14 [/SUP], Yueh Z Lee[SUP] 14 15 [/SUP], James S Hagood[SUP] 3 16 [/SUP], Jason R Mock[SUP] 3 17 [/SUP], Max A Seibold[SUP] 5 18 19 [/SUP], Wanda K O'Neal[SUP] #[/SUP][SUP] 3 [/SUP], Stephanie A Montgomery[SUP] #[/SUP][SUP] 4 13 [/SUP], Richard C Boucher[SUP] #[/SUP][SUP] 3 [/SUP], Ralph S Baric[SUP] #[/SUP][SUP] 1 2 20 [/SUP]
Affiliations
- PMID: 35857635
- DOI: 10.1126/scitranslmed.abo5070
Abstract
A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.