Orally delivered perilla (Perilla frutescens) leaf extract effectively inhibits SARS-CoV-2 infection in a syrian hamster model

Yuan-Fan Chin ^a,1, Wen-Fan Tang ^b,1, Yu-Hsiu Chang ^a,1, Tein-Yao Chang ^a,c,1, Wen-Chin Lin ^a,c,1, Chia-Yi Lin ^b, Chuen-Mi Yang ^a, Hsueh-Ling Wu ^a, Ping-Cheng Liu ^a,Jun-Ren Sun ^a,c,j, Shu-Chen Hsu ^a, Chia-Ying Lee ^a, Hsuan-Ying Lu ^a, Jia-Yu Chang ^a,Jia-Rong Jheng ^f, Cheng Cheung Chen ^a,d, Jyh-Hwa Kau ^a,d,j, Chih-Heng Huang ^a,d,e,Cheng-Hsun Chiu ^g, Yi-Jen Hung ^a, Hui-Ping Tsai ^a,*,2, Jim-Tong Horng ^b,g,h,i,**,3

a Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan

b Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan

c Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense

Medical Center, Taipei 114, Taiwan

d Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan

e Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan

f Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

g Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

h Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan

i Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan

j Division of Infectious Disease and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

On analyzing the results of cell-based assays, we have previously shown that perilla (Perilla frutescens) leaf extract(PLE), a food supplement and orally deliverable traditional Chinese medicine approved by the Taiwan Food and Drug Administration, effectively inhibits SARS-CoV-2 by directly targeting virions. PLE was also found to modulate virusinduced cytokine expression levels. In this study, we explored the anti-SARS-CoV-2 activity of PLE in a hamster model by examining viral loads and virus-induced immunopathology in lung tissues. Experimental animals were intranasally challenged with different SARS-CoV-2 doses. Jugular blood samples and lung tissue specimens were obtained in the acute disease stage (3e4 post-infection days). As expected, SARS-CoV-2 induced lung inflammation and hemorrhagic effusions in the alveoli and perivascular areas; additionally, it increased the expression of several immune markers of lung injury ¡ including lung Ki67-positive cells, Iba-1-positive macrophages, and myeloperoxidase-positive neutrophils.Virus-induced lung alterations were significantly attenuated by orally administered PLE. In addition, pretreatment of hamsters with PLE significantly reduced viral loads and immune marker expression. A purified active fraction of PLE was found to confer higher antiviral protection. Notably, PLE prevented SARS-CoV-2-induced increase in serum markers of liver and kidney function as well as the decrease in serum high-density lipoprotein and total cholesterol levels in a dose-dependent fashion. Differently from lung pathology, monitoring of serum biomarkers in Syrian hamsters may allow a more humane assessment of the novel drugs with potential anti-SARS-CoV-2 activity. Our results expand prior research by confirming that PLE may exert an in vivo therapeutic activity against SARS-CoV-2 by attenuating viral loads and lung tissue inflammation, which may pave the way for future clinical applications.

Keywords: COVID-19, Hamster, Herbal medicine, Perilla frutescens, SARS-CoV-2, Serum biomarkers

https://doi.org/10.38212/2224-6614.3412

(https://www.jfda-online.com/journal/vol30/iss2/6/)