tetano
Editor, Senior Moderator
FASEB J
. 2021 Sep;35(9):e21801.
doi: 10.1096/fj.202002742RR.
Spike protein of SARS-CoV-2 activates macrophages and contributes to induction of acute lung inflammation in male mice
Xiaoling Cao[SUP] 1 [/SUP], Yan Tian[SUP] 1 2 [/SUP], Vi Nguyen[SUP] 1 [/SUP], Yuping Zhang[SUP] 1 3 [/SUP], Chao Gao[SUP] 1 [/SUP], Rong Yin[SUP] 1 [/SUP], Wayne Carver[SUP] 1 4 [/SUP], Daping Fan[SUP] 1 4 [/SUP], Helmut Albrecht[SUP] 5 6 [/SUP], Taixing Cui[SUP] 1 4 [/SUP], Wenbin Tan[SUP] 1 4 [/SUP]
Affiliations
Abstract
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a crucial role in mediating viral entry into host cells. However, whether it contributes to pulmonary hyperinflammation in patients with coronavirus disease 2019 is not well known. In this study, we developed a spike protein-pseudotyped (Spp) lentivirus with the proper tropism of the SARS-CoV-2 spike protein on the surface and determined the distribution of the Spp lentivirus in wild-type C57BL/6J male mice that received an intravenous injection of the virus. Lentiviruses with vesicular stomatitis virus glycoprotein (VSV-G) or with a deletion of the receptor-binding domain (RBD) in the spike protein [Spp (∆RBD)] were used as controls. Two hours postinfection (hpi), there were 27-75 times more viral burden from Spp lentivirus in the lungs than in other organs; there were also about 3-5 times more viral burden from Spp lentivirus than from VSV-G lentivirus in the lungs, liver, kidney, and spleen. Deletion of RBD diminished viral loads in the lungs but not in the heart. Acute pneumonia was observed in animals 24 hpi. Spp lentivirus was mainly found in SPC[SUP]+[/SUP] and LDLR[SUP]+[/SUP] pneumocytes and macrophages in the lungs. IL6, IL10, CD80, and PPAR-γ were quickly upregulated in response to infection in the lungs as well as in macrophage-like RAW264.7 cells. Furthermore, forced expression of the spike protein in RAW264.7 cells significantly increased the mRNA levels of the same panel of inflammatory factors. Our results demonstrated that the spike protein of SARS-CoV-2 confers the main point of viral entry into the lungs and can induce cellular pathology. Our data also indicate that an alternative ACE2-independent viral entry pathway may be recruited in the heart and aorta.
Keywords: COVID-19; SARS-CoV-2; inflammation; lung; spike.
. 2021 Sep;35(9):e21801.
doi: 10.1096/fj.202002742RR.
Spike protein of SARS-CoV-2 activates macrophages and contributes to induction of acute lung inflammation in male mice
Xiaoling Cao[SUP] 1 [/SUP], Yan Tian[SUP] 1 2 [/SUP], Vi Nguyen[SUP] 1 [/SUP], Yuping Zhang[SUP] 1 3 [/SUP], Chao Gao[SUP] 1 [/SUP], Rong Yin[SUP] 1 [/SUP], Wayne Carver[SUP] 1 4 [/SUP], Daping Fan[SUP] 1 4 [/SUP], Helmut Albrecht[SUP] 5 6 [/SUP], Taixing Cui[SUP] 1 4 [/SUP], Wenbin Tan[SUP] 1 4 [/SUP]
Affiliations
- PMID: 34365657
- DOI: 10.1096/fj.202002742RR
Abstract
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a crucial role in mediating viral entry into host cells. However, whether it contributes to pulmonary hyperinflammation in patients with coronavirus disease 2019 is not well known. In this study, we developed a spike protein-pseudotyped (Spp) lentivirus with the proper tropism of the SARS-CoV-2 spike protein on the surface and determined the distribution of the Spp lentivirus in wild-type C57BL/6J male mice that received an intravenous injection of the virus. Lentiviruses with vesicular stomatitis virus glycoprotein (VSV-G) or with a deletion of the receptor-binding domain (RBD) in the spike protein [Spp (∆RBD)] were used as controls. Two hours postinfection (hpi), there were 27-75 times more viral burden from Spp lentivirus in the lungs than in other organs; there were also about 3-5 times more viral burden from Spp lentivirus than from VSV-G lentivirus in the lungs, liver, kidney, and spleen. Deletion of RBD diminished viral loads in the lungs but not in the heart. Acute pneumonia was observed in animals 24 hpi. Spp lentivirus was mainly found in SPC[SUP]+[/SUP] and LDLR[SUP]+[/SUP] pneumocytes and macrophages in the lungs. IL6, IL10, CD80, and PPAR-γ were quickly upregulated in response to infection in the lungs as well as in macrophage-like RAW264.7 cells. Furthermore, forced expression of the spike protein in RAW264.7 cells significantly increased the mRNA levels of the same panel of inflammatory factors. Our results demonstrated that the spike protein of SARS-CoV-2 confers the main point of viral entry into the lungs and can induce cellular pathology. Our data also indicate that an alternative ACE2-independent viral entry pathway may be recruited in the heart and aorta.
Keywords: COVID-19; SARS-CoV-2; inflammation; lung; spike.