Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12

Yun Teng; Fangyi Xu; Xiangcheng Zhang; Jingyao Mu; Mohammed Sayed; Xin Hu; Chao Lei; Mukesh Sriwastva; Anil Kumar; Kumaran Sundaram; Lifeng Zhang; Juw Won Park; Shao-Yu Chen; Shuangqin Zhang; Jun Yan; Michael L Merchant; Xiang Zhang; Craig J McClain; Jennifer K Wolfe; Robert S Adcock; Donghoon Chung; Kenneth E Palmer; Huang-Ge Zhang

doi:10.1016/j.ymthe.2021.05.005

Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12

Mol Ther. 2021 Aug 4;29(8):2424-2440. doi: 10.1016/j.ymthe.2021.05.005. Epub 2021 May 11.

Authors

Yun Teng¹, Fangyi Xu², Xiangcheng Zhang³, Jingyao Mu², Mohammed Sayed⁴, Xin Hu⁵, Chao Lei², Mukesh Sriwastva², Anil Kumar², Kumaran Sundaram², Lifeng Zhang², Juw Won Park⁶, Shao-Yu Chen⁷, Shuangqin Zhang⁸, Jun Yan², Michael L Merchant⁹, Xiang Zhang⁷, Craig J McClain¹⁰, Jennifer K Wolfe¹¹, Robert S Adcock¹¹, Donghoon Chung¹², Kenneth E Palmer¹³, Huang-Ge Zhang¹⁴

Affiliations

¹ James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. Electronic address: yun.teng@louisville.edu.
² James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
³ James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; Department of ICU, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223300, China.
⁴ Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40202, USA.
⁵ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40202, USA; KBRIN Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA.
⁷ Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
⁸ Peeples Cancer Institute at Hamilton Medical Center, Dalton, GA 30720, USA.
⁹ Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY 40202, USA.
¹⁰ Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹¹ Center for Predictive Medicine for Emerging Infectious Diseases, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹² Department of Microbiology & Immunology, University of Louisville, Louisville, KY 40202, USA; Center for Predictive Medicine for Emerging Infectious Diseases, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹³ Center for Predictive Medicine for Emerging Infectious Diseases, School of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹⁴ Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA; Department of Microbiology & Immunology, University of Louisville, Louisville, KY 40202, USA; James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. Electronic address: h0zhan17@louisville.edu.

Abstract

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomes^Nsp12Nsp13). Mechanistically, we show that exosomes^Nsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β from exosomes^Nsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomes^Nsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomes^Nsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.

Keywords: ACE2; IL-1β; IL-6; NF-κB; Nsp12; SARS-CoV-2; TNF-α; exosomes; ginger exosome-like nanoparticle; lung epithelial cells; lung inflammation; macrophages; microRNA; spike.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

MeSH terms

A549 Cells
Animals
COVID-19 / metabolism*
Cell Line
Cell Line, Tumor
Chlorocebus aethiops
Cytokines / metabolism
Epithelial Cells / metabolism
Exosomes / metabolism*
Humans
Interleukin-6 / metabolism
Macrophages, Alveolar / metabolism
Male
Mice
Mice, Inbred C57BL
MicroRNAs / metabolism*
NF-kappa B / metabolism
Plants / metabolism*
Pneumonia / metabolism*
SARS-CoV-2 / pathogenicity
Tumor Necrosis Factor-alpha / metabolism
U937 Cells
Vero Cells

Substances

Cytokines
Interleukin-6
MicroRNAs
NF-kappa B
Tumor Necrosis Factor-alpha

Abstract

Publication types

MeSH terms

Substances

Grants and funding