Int J Biol Sci 2021; 17(13):3305-3319. doi:10.7150/ijbs.63329 This issue

Research Paper

RS-5645 attenuates inflammatory cytokine storm induced by SARS-CoV-2 spike protein and LPS by modulating pulmonary microbiota

Te Liu1*, Jianchao Wu1*, Changpeng Han2*, Zhangbin Gong3*, Giuseppe La Regina4*, Jiulin Chen1, Fangfang Dou1, Romano Silvestri4✉, Chuan Chen1✉, Zhihua Yu1✉

1. Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
2. Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
3. Department of Biochemistry, College of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
4. Laboratory affiliated with the Institute Pasteur Italy-Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
* These authors contributed equally to this work and shared the first authorship.

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Citation:
Liu T, Wu J, Han C, Gong Z, Regina GL, Chen J, Dou F, Silvestri R, Chen C, Yu Z. RS-5645 attenuates inflammatory cytokine storm induced by SARS-CoV-2 spike protein and LPS by modulating pulmonary microbiota. Int J Biol Sci 2021; 17(13):3305-3319. doi:10.7150/ijbs.63329. Available from https://www.ijbs.com/v17p3305.htm

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Abstract

Graphic abstract

An inflammatory cytokine storm is considered an important cause of death in severely and critically ill COVID-19 patients, however, the relationship between the SARS-CoV-2 spike (S) protein and the host's inflammatory cytokine storm is not clear. Here, the qPCR results indicated that S protein induced a significantly elevated expression of multiple inflammatory factor mRNAs in peripheral blood mononuclear cells (PBMCs), whereas RS-5645 ((4-(thiophen-3-yl)-1-(p-tolyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone) attenuated the expression of the most inflammatory factor mRNAs. RS-5645 also significantly reduced the cellular ratios of CD45+/IFNγ+, CD3+/IFNγ+, CD11b+/IFNγ+, and CD56+/IFNγ+ in human PBMCs. In addition, RS-5645 effectively inhibited the activation of inflammatory cells and reduced inflammatory damage to lung tissue in mice. Sequencing results of 16S rRNA v3+v4 in mouse alveolar lavage fluid showed that there were 494 OTUs overlapping between the alveolar lavage fluid of mice that underwent S protein+ LPS-combined intervention (M) and RS-5645-treated mice (R), while R manifested 64 unique OTUs and M exhibited 610 unique OTUs. In the alveoli of group R mice, the relative abundances of microorganisms belonging to Porphyromonas, Rothia, Streptococcus, and Neisseria increased significantly, while the relative abundances of microorganisms belonging to Psychrobacter, Shimia, and Sporosarcina were significantly diminished. The results of KEGG analysis indicated that the alveolar microbiota of mice in the R group can increase translation and reduce the activity of amino acid metabolism pathways. COG analysis results indicated that the abundance of proteins involved in ribosomal structure and biogenesis related to metabolism was augmented in the alveolar microbiota of the mice in the R group, while the abundance of proteins involved in secondary metabolite biosynthesis was significantly reduced. Therefore, our research results showed that RS-5645 attenuated pulmonary inflammatory cell infiltration and the inflammatory storm induced by the S protein and LPS by modulating the pulmonary microbiota.

Keywords: SARS-CoV-2 (COVID-19) spike protein, 4-(thiophen-3-yl)-1-(p-tolyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone (RS-5645), inflammatory factor storm, pulmonary microbiota