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

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.

Evolutionary dynamics of microRNA target sites across vertebrate evolution

“…These observations indicate that this miRNA is gaining novel targets and losing existing targets relatively rapidly, with neutral or potentially faster than neutral rates. Notably, miR-146 contributes to diverse immune system functions, including fever response, tumor suppression, T-cell homeostasis, and cytokine production in multiple immune cell lineages [71][72][73][74][75]. It is conceivable that miR-146 targets may be rapidly co-evolving with pathogens as part of an 'arms race' scenario that has frequently been seen in host-pathogen interactions [76].…”

Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype

“…Cardiac macrophages participate in homeostatic maintenance and tissue repair by producing reparative inflammatory mediators or undergoing polarization (Shiraishi et al, 2016;Ferraro et al, 2019). Some pioneering studies have reported that miR-146b regulates macrophage paracrine signaling and activation under various inflammatory environments (He et al, 2016;Peng et al, 2016;Deng et al, 2019;Zhang et al, 2019); however, little is known about the effects of miR-146b on cardiac macrophages. In the present study, the four most abundant cytokines in wounds (IL-1β, IL-6, TNF-α, and MCP-1) (Mescher, 2017) were found to be significantly reduced in the presence of a miR-146b-5p mimic, whereas many were significantly increased by treatment with an miR-146b-5p inhibitor.…”

Immune Modulation and Immune-Mediated Pathogenesis of Emerging Tickborne Banyangviruses

“…Moreover, whereas the infection of SFTSV possessing wild-type NSs was lethal in IFNAR −/− mice, recombinant SFTSV possessing NSs-P 102 A rescued 70% of mice, suggesting IL-10 expression might be a key factor that contributes to the pathogenesis of SFTSV [47]. Interestingly, other reports demonstrated that SFTSV or SFTSV NSs induces the expression of micro-RNA (miRNA)-146b, which is known to mediate macrophage differentiation by upregulation of IL-10, resulting in THP-1 monocytes skewing towards an anti-inflammatory M2 phenotype [48]. The upregulation of IL-10 and generation of an M2 phenotype may indeed be beneficial in the context of a viral infection in order to establish persistence as has been described for other viruses [126].…”

“…The cellular receptor for SFTSV and HRTV has been identified as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), which is expressed on macrophages and dendritic cells, implying that these cells are the primary cellular target for viral replication [44,45]. Indeed, in vitro studies have demonstrated the ability of immortalized human and mouse macrophage cell lines to support replication of SFTSV [46][47][48]. Moreover, other C-type lectins such as DC-SIGN related (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin), when expressed on non-permissive cells, can support viral entry [49].…”