Abstract
BackgroundInfection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood.MethodsRecombinant N-protein was pretreated with polymyxin B, a lipopolysaccharide (LPS)-neutralizing agent. C57BL/6, C3H/HeJ (resistant to LPS), and C3H/HeN (control for C3H/HeJ) mice were exposed to N-protein via intratracheal administration to examine acute lung injury. In vitro, bone marrow–derived macrophages (BMDMs) were cultured with N-protein to study phosphorylation of nuclear factor kappa B (NF-ĸB) p65, macrophage polarization, and expression of proinflammatory cytokines.ResultsN-protein produced acute lung injury in C57BL/6 mice, with elevated protein permeability, total cell count, neutrophil infiltration, and proinflammatory cytokines in the bronchioalveolar lavage. N-protein also induced lung injury in both C3H/HeJ and C3H/HeN mice, indicating that the effect could not be attributed to the LPS contamination. N-protein triggered phosphorylation of NF-ĸB p65 in vitro, which was abolished by both N-protein denaturation and treatment with an antibody for N-protein, demonstrating that the effect is N-protein specific. In addition, N-protein promoted M1 macrophage polarization and the expression of proinflammatory cytokines, which was also blocked by N-protein denaturation and antibody for N-protein. Furthermore, N-protein induced NF-ĸB p65 phosphorylation in the lung, while pyrrolidine dithiocarbamate, an NF-ĸB inhibitor, alleviated the effect of N-protein on acute lung injury. ConclusionsSARS-CoV-2 N-protein itself is toxic and induces acute lung injury in mice. Both N-protein and NF-ĸB pathway may be therapeutic targets for treating multi-organ injuries in Coronavirus disease 2019 (COVID-19).
Highlights
Coronavirus disease 2019 (COVID-19) has become a global public health emergency since December, 2019
The virus that causes COVID-19 is named as SARS-CoV-2, which belongs to the family of Coronaviruses, including Middle East respiratory syndrome Coronavirus (MERS-CoV) and severe acute respiratory syndrome Coronavirus (SARS-CoV) [1]
We aimed to examine the direct effect of recombinant N-protein on acute lung injury and nuclear factor kappa B (NF-ĸB) activation
Summary
Coronavirus disease 2019 (COVID-19) has become a global public health emergency since December, 2019. The virus that causes COVID-19 is named as SARS-CoV-2, which belongs to the family of Coronaviruses, including Middle East respiratory syndrome Coronavirus (MERS-CoV) and severe acute respiratory syndrome Coronavirus (SARS-CoV) [1]. Infections from MERS-CoV, SARS-CoV, and SARS-CoV-2 have similar clinical features and may result in acute respiratory distress syndrome (ARDS, acute lung injury) and involvement of other organs [2,3,4]. COVID-19 has a mortality rate of 1-2%, which is lower than that of SARS (9.5%) and MERS (34.4%) [5]. It is estimated that the mortality rate of COVID-19-induced ARDS is about 45%, with incidence of ARDS as high as 90% for nonsurvivors. Severe COVID-19-associated ARDS had higher SARS-CoV-2 viral load, neutrophil count, proinflammatory cytokines, and incidence of thrombosis [6]. Infection of SARS-CoV-2 may cause acute respiratory syndrome. The direct involvement of N-protein in lung injury is poorly understood
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