tetano
Editor, Senior Moderator
J Virol
. 2022 Apr 14;e0003822.
doi: 10.1128/jvi.00038-22. Online ahead of print.
Single-Cell Landscape of Lungs Reveals Key Role of Neutrophil-Mediated Immunopathology during Lethal SARS-CoV-2 Infection
Xiao-Shuang Zheng[SUP] #[/SUP][SUP] 1 2 [/SUP], Qi Wang[SUP] #[/SUP][SUP] 1 2 [/SUP], Juan Min[SUP] #[/SUP][SUP] 1 [/SUP], Xu-Rui Shen[SUP] 1 2 [/SUP], Qian Li[SUP] 1 2 [/SUP], Qiu-Chen Zhao[SUP] 3 [/SUP], Xi Wang[SUP] 1 2 [/SUP], Ren-Di Jiang[SUP] 1 2 [/SUP], Rong Geng[SUP] 1 2 [/SUP], Ying Chen[SUP] 1 2 [/SUP], Yan Zhu[SUP] 1 [/SUP], Bei Li[SUP] 1 [/SUP], Wei Zhang[SUP] 1 [/SUP], Ang Li[SUP] 1 2 [/SUP], Ting-Ting Xie[SUP] 1 2 [/SUP], Mei-Qin Liu[SUP] 1 2 [/SUP], Liang Cheng[SUP] 3 [/SUP], Zheng-Li Shi[SUP] 1 2 [/SUP], Peng Zhou[SUP] 1 2 [/SUP]
Affiliations
Abstract
Due to the limitation of human studies with respect to individual difference or the accessibility of fresh tissue samples, how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in pathological complications in lung, the main site of infection, is still incompletely understood. Therefore, physiologically relevant animal models under realistic SARS-CoV-2 infection conditions would be helpful to our understanding of dysregulated inflammation response in lung in the context of targeted therapeutics. Here, we characterized the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicates human symptoms, including severe lung pathology and lymphopenia. We showed a reduction of lymphocyte populations and an increase of neutrophils in lung and then demonstrated the key role of neutrophil-mediated lung immunopathology in both mice and humans. Under severe conditions, neutrophils recruited by a chemokine-driven positive feedback produced elevated "fatal signature" proinflammatory genes and pathways related to neutrophil activation or releasing of granular content. In addition, we identified a new Cd177[SUP]high[/SUP] cluster that is undergoing respiratory burst and Stfa[SUP]high[/SUP] cluster cells that may dampen antigen presentation upon infection. We also revealed the devastating effect of overactivated neutrophil by showing the highly enriched neutrophil extracellular traps in lung and a dampened B-cell function in either lung or spleen that may be attributed to arginine consumption by neutrophil. The current study helped our understanding of SARS-CoV-2-induced pneumonia and warranted the concept of neutrophil-targeting therapeutics in COVID-19 treatment. IMPORTANCE We demonstrated the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicated human symptoms, including severe lung pathology and lymphopenia. Our comprehensive study revealed the key role of neutrophil-mediated lung immunopathology in SARS-CoV-2-induced severe pneumonia, which not only helped our understanding of COVID-19 but also warranted the concept of neutrophil targeting therapeutics in COVID-19 treatment.
Keywords: COVID-19; SARS-CoV-2; lung pathology; neutrophil; single-cell RNA sequencing.
. 2022 Apr 14;e0003822.
doi: 10.1128/jvi.00038-22. Online ahead of print.
Single-Cell Landscape of Lungs Reveals Key Role of Neutrophil-Mediated Immunopathology during Lethal SARS-CoV-2 Infection
Xiao-Shuang Zheng[SUP] #[/SUP][SUP] 1 2 [/SUP], Qi Wang[SUP] #[/SUP][SUP] 1 2 [/SUP], Juan Min[SUP] #[/SUP][SUP] 1 [/SUP], Xu-Rui Shen[SUP] 1 2 [/SUP], Qian Li[SUP] 1 2 [/SUP], Qiu-Chen Zhao[SUP] 3 [/SUP], Xi Wang[SUP] 1 2 [/SUP], Ren-Di Jiang[SUP] 1 2 [/SUP], Rong Geng[SUP] 1 2 [/SUP], Ying Chen[SUP] 1 2 [/SUP], Yan Zhu[SUP] 1 [/SUP], Bei Li[SUP] 1 [/SUP], Wei Zhang[SUP] 1 [/SUP], Ang Li[SUP] 1 2 [/SUP], Ting-Ting Xie[SUP] 1 2 [/SUP], Mei-Qin Liu[SUP] 1 2 [/SUP], Liang Cheng[SUP] 3 [/SUP], Zheng-Li Shi[SUP] 1 2 [/SUP], Peng Zhou[SUP] 1 2 [/SUP]
Affiliations
- PMID: 35420442
- DOI: 10.1128/jvi.00038-22
Abstract
Due to the limitation of human studies with respect to individual difference or the accessibility of fresh tissue samples, how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in pathological complications in lung, the main site of infection, is still incompletely understood. Therefore, physiologically relevant animal models under realistic SARS-CoV-2 infection conditions would be helpful to our understanding of dysregulated inflammation response in lung in the context of targeted therapeutics. Here, we characterized the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicates human symptoms, including severe lung pathology and lymphopenia. We showed a reduction of lymphocyte populations and an increase of neutrophils in lung and then demonstrated the key role of neutrophil-mediated lung immunopathology in both mice and humans. Under severe conditions, neutrophils recruited by a chemokine-driven positive feedback produced elevated "fatal signature" proinflammatory genes and pathways related to neutrophil activation or releasing of granular content. In addition, we identified a new Cd177[SUP]high[/SUP] cluster that is undergoing respiratory burst and Stfa[SUP]high[/SUP] cluster cells that may dampen antigen presentation upon infection. We also revealed the devastating effect of overactivated neutrophil by showing the highly enriched neutrophil extracellular traps in lung and a dampened B-cell function in either lung or spleen that may be attributed to arginine consumption by neutrophil. The current study helped our understanding of SARS-CoV-2-induced pneumonia and warranted the concept of neutrophil-targeting therapeutics in COVID-19 treatment. IMPORTANCE We demonstrated the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicated human symptoms, including severe lung pathology and lymphopenia. Our comprehensive study revealed the key role of neutrophil-mediated lung immunopathology in SARS-CoV-2-induced severe pneumonia, which not only helped our understanding of COVID-19 but also warranted the concept of neutrophil targeting therapeutics in COVID-19 treatment.
Keywords: COVID-19; SARS-CoV-2; lung pathology; neutrophil; single-cell RNA sequencing.