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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311706

ABSTRACT

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Accumulating evidences suggest that SARS-CoV-2 infection causes dysregulation of immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced by SARS-CoV-2 in animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could reduce inflammatory response and rescue the pneumonia with substantial reduction of viral titers in SASR-CoV-2 infected animals. Remarkably, Paquinimod treatment resulted in 100% survival of mice in a lethal model of mouse coronavirus (MHV) infection. A novel group of neutrophils that contributed to the uncontrolled inflammation and onset of COVID-19 were dramatically induced by coronavirus infections. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and noncanonical neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.Funding: This work was supported by the National Natural Science Foundation of China (31570891;31872736), the National Key Research and Development Program of China (2016YFA0500302;2020YFA0707800), the National Key Research and Development Program (2020YFA0707500) and the Strategic Priority Research Program (XDB29010000). Xiangxi Wang was supported by Ten Thousand Talent Program and the NSFS Innovative Research Group (81921005). We thank National Mega projects of China for Major Infectious Diseases (2017ZX10304402), CAMS initiative for Innovative Medicine of China (2016-12M-2-006) and The National Natural Science Foundation of China (82041008) for the support on the animal model study. Conflict of Interest: The authors have no conflicts of interest to declare.Ethical Approval: All experiments with live SARS-CoV-2 viruses were carried out in the enhanced biosafety level 3 (P3+) facilities in the Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) approved by the National Health Commission of the People’s Republic of China. All animals care and use were in accordance with the Guide for the Care and Use of Laboratory Animals of the Chinese Association for Laboratory Animal Science. All procedures of animal handling were approved by the Animal Care Committee of Peking University Health Science Center.

2.
Cell Host Microbe ; 29(2): 222-235.e4, 2021 02 10.
Article in English | MEDLINE | ID: covidwho-987276

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2-infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.


Subject(s)
Alarmins/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Neutrophils/drug effects , SARS-CoV-2/drug effects , Animals , COVID-19/metabolism , COVID-19/virology , Disease Models, Animal , Female , Humans , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/metabolism , Transcriptome , Viral Load
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