Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 221, Issue 4, Pages 647-659Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiz483
Keywords
CLR; MERS-CoV; Mincle; proinflammatory response; RLR
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Funding
- Health and Medical Research Fund [14131392, 17161272]
- Food and Health Bureau of the Hong Kong Special Administrative Region (HKSAR) Government
- Themebased Research Scheme [T11-707/15-R]
- Research Grants Council
- HKSAR Government
- Shaw Foundation Hong Kong
- Respiratory Viral Research Foundation Limited
- Chow Sin Lan Charity Fund Limited, and Chan Yin Chuen Memorial Charitable Foundation
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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.
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