Affiliation:
1. State Key Laboratory of Emerging Infectious Diseases, Pokfulam, Hong Kong
2. Department of Microbiology, Pokfulam, Hong Kong
3. Carol Yu Centre for Infection, Pokfulam, Hong Kong
4. The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Abstract
Abstract
Background
Human infection with Middle East respiratory syndrome coronavirus (MERS-CoV) poses an ongoing threat to public health worldwide. The studies of MERS patients with severe disease and experimentally infected animals showed that robust viral replication and intensive proinflammatory response in lung tissues contribute to high pathogenicity of MERS-CoV. We sought to identify pattern recognition receptor (PRR) signaling pathway(s) that mediates the inflammatory cascade in human macrophages upon MERS-CoV infection.
Methods
The potential signaling pathways were manipulated individually by pharmacological inhibition, small interfering ribonucleic acid (siRNA) depletion, and antibody blocking. The MERS-CoV-induced proinflammatory response was evaluated by measuring the expression levels of key cytokines and/or chemokines. Reverse transcription-quantitative polymerase chain reaction assay, flow cytometry analysis, and Western blotting were applied to evaluate the activation of related PRRs and engagement of adaptors.
Results
MERS-CoV replication significantly upregulated C-type lectin receptor (CLR) macrophage-inducible Ca2+-dependent lectin receptor (Mincle). The role of Mincle for MERS-CoV-triggered cytokine/chemokine induction was established based on the results of antibody blockage, siRNA depletion of Mincle and its adaptor spleen tyrosine kinase (Syk), and Syk pharmacological inhibition. The cytokine and/or chemokine induction was significantly attenuated by siRNA depletion of retinoic acid-inducible-I-like receptors (RLR) or adaptor, indicating that RLR signaling also contributed to MERS-CoV-induced proinflammatory response.
Conclusions
The CLR and RLR pathways are activated and contribute to the proinflammatory response in MERS-CoV-infected macrophages.
Funder
Health and Medical Research Fund
Food and Health Bureau of the Hong KongSpecial Administrative Region (HKSAR) Government
Theme-based Research Scheme
Research Grants Council, the HKSAR Government
High Level Hospital-Summit Program in Guangdong
The University of Hong Kong-Shenzhen Hospital
Shaw Foundation Hong Kong
Richard Yu and Carol Yu
Michael Seak-Kan Tong
Respiratory Viral Research Foundation Limited
Hui Ming, Hui Hoy & Chow Sin Lan Charity Fund Limited
Chan Yin Chuen Memorial Charitable Foundation
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Immunology and Allergy
Cited by
43 articles.
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