Low dose radiation therapy attenuates ACE2 depression and inflammatory cytokines induction by COVID-19 viral spike protein in human bronchial epithelial cells

Abstract

Purpose: Low-dose radiation therapy (LDRT) is an evidence-based anti-inflammatory treatment. In anti-COVID-19, our study suggests that low to moderate dose radiation of < 1.5 Gy can inhibit the induction of inflammatory cytokine and attenuate the ACE2 depression induced by spike protein in human bronchial epithelial cells in COVID-19 infection. Our study provided further mechanistic evidence to support LDRT as a cost-effective treatment for COVID-19 to relieve the severe inflammatory reaction and lung injury. Methods and materials: A cellular model was created by treating human bronchial epithelial cells (BEP2D) with SARS-CoV-2 spike protein. We used the qRT-PCR and ELISA analysis to identify the production of inflammatory cytokines. The BEP2D control cells and the spike-treated cells were irradiated using a single low to moderate dose radiation of 0.5 Gy, 1 Gy, and 1.5 Gy. The inflammatory cytokines and ACE2 expression were detected at different time points. Results: The soluble SARS-CoV-2 spike protein stimulated the formation of inflammatory cytokines IL-6 and TNF-α while reducing the ACE2 protein expression in human bronchial epithelial cells. A single low to moderate dose exposure of 0.5 Gy, 1 Gy, and 1.5 Gy could attenuate the IL-6 and TNF-α induction and rescue the depression of ACE2 by spike protein. Moreover, the spike protein increased the proteolytic degradation of ACE2 protein by promoting NEDD4-mediated ubiquitination of ACE2. Conclusions: The low-dose radiation can attenuate ACE2 depression and inflammatory response produced in the targeted human bronchial epithelial cells by spike protein. This coordinating effect of LDRT may relieve the severe inflammatory reaction and lung injury in COVID-19 patients.

Keywords:

• Low dose radiation
• ACE2
• COVID-19

Acknowledgments

We thank Dr CC Harris for providing cell lines, Dr Xiaoming Yang for gifts of plasmids.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [Grant No. 31800704] and the Postdoctoral Foundation of China [Grant No. 2018M643847].

Notes on contributors

Ke Wen

Ke Wen is a master student in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.

Chenjun Bai

Chenjun Bai is an assistant professor in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.

Hongling Zhao

Hongling Zhao is a master student in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.

Pingkun Zhou

Pingkun Zhou is a professor in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.

Shanshan Gao

Shanshan Gao is an assistant professor in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.

Hua Guan

Hua Guan assistant professor in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.

Man Song

Man Song is an assistant professor in Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine.