GMI, a fungal immunomodulatory protein, ameliorates SARS-CoV-2 envelope protein-induced inflammation in macrophages via inhibition of MAPK pathway

Zhi-Hu Lin; Hsin Yeh; Hung-Chih Lo; Wei-Jyun Hua; Ming-Yang Ni; Li-Kai Wang; Ting-Ting Chang; Muh-Hwa Yang; Tung-Yi Lin

doi:10.1016/j.ijbiomac.2023.124648

GMI, a fungal immunomodulatory protein, ameliorates SARS-CoV-2 envelope protein-induced inflammation in macrophages via inhibition of MAPK pathway

Int J Biol Macromol. 2023 Jun 30:241:124648. doi: 10.1016/j.ijbiomac.2023.124648. Epub 2023 Apr 28.

Authors

Zhi-Hu Lin¹, Hsin Yeh¹, Hung-Chih Lo¹, Wei-Jyun Hua², Ming-Yang Ni³, Li-Kai Wang⁴, Ting-Ting Chang⁵, Muh-Hwa Yang⁶, Tung-Yi Lin⁷

Affiliations

¹ Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
² Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Program in Molecular Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Hungchi Women & Children's Hospital, Taoyuan, Taiwan.
⁴ Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan; Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
⁵ Biomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁶ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁷ Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Program in Molecular Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Biomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address: tylin99@nycu.edu.tw.

Abstract

Clinically, COVID-19 is often accompanied by a severe immune response (cytokine storm) which produces a large number of cytokines, such as TNF-α, IL-6 and IL-12, and consequently causes acute respiratory distress syndrome (ARDS). GMI is a type of fungal immunomodulatory protein that is cloned from Ganoderma microsporum and acts as modulating immunocyte for various inflammatory diseases. This study identifies GMI as a potential anti-inflammatory agent and determines the effects of GMI on the inhibition of SARS-CoV-2-induced cytokine secretion. Functional studies showed that SARS-CoV-2 envelope (E) protein induces inflammatory process in murine macrophages RAW264.7 and MH-S cells and in phorbol 12-myristate 13-acetate (PMA)-stimulated human THP-1 cells. GMI exhibits a strong inhibitory effect for SARS-CoV-2-E-induced pro-inflammatory mediators, including NO, TNF-α, IL-6, and IL-12 in macrophages. GMI reduces SARS-CoV-2-E-induced intracellular inflammatory molecules, such as iNOS and COX-2, and inhibits SARS-CoV-2-E-stimulated phosphorylation of ERK1/2 and P38. GMI also downregulates pro-inflammatory cytokine levels in lung tissue and serum after the mice inhale SARS-CoV-2-E protein. In conclusion, this study shows that GMI acts as an agent to alleviate SARS-CoV-2-E-induced inflammation.

Keywords: COVID-19; Envelope protein; GMI; Inflammation; Nutraceuticals.

MeSH terms

Animals
COVID-19*
Cytokines / metabolism
Humans
Immunity
Inflammation
Interleukin-12
Interleukin-6
Macrophages / metabolism
Mice
SARS-CoV-2* / metabolism
Tumor Necrosis Factor-alpha

Substances

Interleukin-6
Tumor Necrosis Factor-alpha
Cytokines
Interleukin-12