Severe Fever With Thrombocytopenia Syndrome Virus-Induced Macrophage Differentiation Is Regulated by miR-146.

Li Zhang,Yajie Guan,Huanru Wang,Zhiwei Wu,Weiwen Zhu,Nan Zheng,Yuxuan Fu,Mengdi Guo

doi:10.3389/fimmu.2019.01095

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with a high mortality rate in humans, which is caused by SFTS virus (SFTSV), a novel phlebovirus in the Bunyaviridae family, is tick borne and endemic in Eastern Asia. Previous study found that SFTSV can infect and replicate in macrophages in vivo and in vitro. However, the role of macrophages in virus replication and the potential pathogenic mechanisms of SFTSV in macrophage remain unclear. In this study, we provided evidence that the SFTSV infection drove macrophage differentiation skewed to M2 phenotype, facilitated virus shedding, and resulted in viral spread. We showed evidence that miR-146a and b were significantly upregulated in macrophages during the SFTSV infection, driving the differentiation of macrophages into M2 cells by targeting STAT1. Further analysis revealed that the elevated miR-146b but not miR-146a was responsible for IL-10 stimulation. We also found that SFTSV increased endogenous miR-146b-induced differentiation of macrophages into M2 cells mediated by viral non-structural protein (NSs). The M2 skewed differentiation of macrophages may have important implication to the pathogenesis of SFTS.

Highlights

Severe fever with thrombocytopenia syndrome (SFTS) is characterized by hemorrhagic fever with a high mortality rate in humans, which is caused by SFTS virus (SFTSV), a novel phlebovirus in the Bunyaviridae family
We showed that SFTSV infection significantly upregulated miR-146a/b expression in macrophages, which resulted in the increase of macrophage differentiation into M2 phenotype through miR-146a/b targeting of STAT1
The mRNA level of M2 markers steadily increased upon viral infection and peaked at 42 h post-infection (Figure 1A). These data showed that infection by SFTS virus drives infected THP-1 differentiation toward first an pro-inflammatory M1 phenotype characterized by increase of TNF-α, IL-1β, IL-6, and CD86 mRNA within the first 12–24 h followed by change to the anti-inflammatory M2 phenotype characterized by CD163, CD206, IL-10, and CCL22 mRNA expression

Summary

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is characterized by hemorrhagic fever with a high mortality rate in humans, which is caused by SFTS virus (SFTSV), a novel phlebovirus in the Bunyaviridae family. Monocytes/macrophages are believed to be the main targets of SFTSV infection [5, 6]. In addition to their roles in clearance of circulating virus by phagocytosis [6, 7], macrophages play critical roles in innate immune defense by modulating adaptive immune response to various pathogens through antigen processing and presentation [8,9,10].

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Conclusion