CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections.

Pei-Shan Sung,Shie-Liang Hsieh

doi:10.3389/fimmu.2019.02867

Abstract

The protective roles of endosomal toll-like receptors (TLRs) and cytosolic nucleic acid sensors are well elucidated, but the pathogenic host factors during viral infections remain unclear. Spleen tyrosine kinase (Syk)-coupled C-type lectins (CLECs) CLEC2 and CLEC5A are highly expressed on platelets and myeloid cells, respectively. CLEC2 has been shown to recognize snake venom aggretin and the endogenous ligand podoplanin and acts as a critical regulator in the development and immunothrombosis. Although CLEC2 has been reported to interact with type I immunodeficiency virus (HIV-1), its role in viral infections is still unclear. CLEC5A binds to fucose and mannose moieties of dengue virus membrane glycans, as well as to N-acetylglucosamine (GlcNAc)/N-acetylmuramic acid (MurNAc) disaccharides that form the backbone of L. monocytogenes peptidoglycans. Recently, we demonstrated that both CLEC2 and CLEC5A are critical in microbe-induced “neutrophil extracellular trap” (NET) formation and proinflammatory cytokine production. Moreover, activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). These findings not only illustrate the immunomodulatory effects of EVs during platelet-leukocyte interactions, but also demonstrate the critical roles of CLEC2 and CLEC5A in acute viral infections.

Highlights

The global outburst of severe acute respiratory syndrome coronavirus (SARS-CoV) infection in 2003 inspired our exploration of how a viral infection can activate a massive over-production of cytokines by the host immune system–a phenomenon known as a “cytokine storm”; this results in a severe inflammatory reaction and increases systemic vascular permeability within 2–5 days following viral exposure
Following our identification of CLEC5A as the pathogenic host factor in flaviviruses, we further found that CLEC2 and Toll-like receptor 2 (TLR2) are pathogenic receptors in dengue virus (DV), Japanese encephalitis virus (JEV), and H5N1 infections
These viruses are captured by high affinity receptors (DCSIGN and mannose receptor (MR)) to induce inflammatory cytokine release via activation of CLEC5A and CLEC2

Summary

Frontiers in Immunology

Received: 27 September 2019 Accepted: 22 November 2019 Published: 06 December 2019. Citation: Sung P-S and Hsieh S-L (2019) CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections. The protective roles of endosomal toll-like receptors (TLRs) and cytosolic nucleic acid sensors are well elucidated, but the pathogenic host factors during viral infections remain unclear. We demonstrated that both CLEC2 and CLEC5A are critical in microbe-induced “neutrophil extracellular trap” (NET) formation and proinflammatory cytokine production. Activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). These findings illustrate the immunomodulatory effects of EVs during platelet-leukocyte interactions, and demonstrate the critical roles of CLEC2 and CLEC5A in acute viral infections

INTRODUCTION

ACUTE VIRAL INFECTIONS

NUCLEIC ACID RECEPTORS AND SENSORS IN ACUTE VIRAL INFECTIONS

Cytosolic Sensors

Findings

CONCLUSIONS