Hantaan Virus Infection Induces CXCL10 Expression through TLR3, RIG-I, and MDA-5 Pathways Correlated with the Disease Severity

Yusi Zhang,Jing Yi,Yun Zhang,Boquan Jin,Angang Yang,Chunmei Zhang,Ran Zhuang,Bei Liu,Zhuwei Xu,Jiuping Wang,Ying Ma,Kun Yang

doi:10.1155/2014/697837

Abstract

Hantaan virus (HTNV) is a major agent causing hemorrhagic fever with renal syndrome (HFRS). Although the pathogenesis of HFRS is unclear, some reports have suggested that the abundant production of proinflammatory cytokines and uncontrolled inflammatory responses may contribute to the development of HFRS. CXCL10 is one of these cytokines and is found to be involved in the pathogenesis of many virus infectious diseases. However, the role of CXCL10 in the pathogenesis of HFRS and the molecular regulation mechanism of CXCL10 in HTNV infection remain unknown. In this study, we report that CXCL10 expresses highly in the HFRS patients' sera and the elevated CXCL10 is positively correlated with the severity of HFRS. We find that HTNV, a single-strand RNA virus, can act as a double-strand RNA to activate the TLR3, RIG-I, and MDA-5 signaling pathways. Through the downstream transcription factors of these pathways, NF-κB and IRF7, which bind directly to the CXCL10's promoter, the expression of CXCL10 is increased. Our results may help to better understand the role of CXCL10 in the development of HFRS and may provide some novel insights into the immune response of HTNV infection.

Highlights

Hantaan virus (HTNV) is a member of the enveloped Bunyaviridae family characterized by a tripartite single-stranded RNA genome of negative polarity
Geimonen et al have reported that HTNV induce CXCL10 expression in Human umbilical vein endothelial cells (HUVECs) [17], little is known about the molecular regulation mechanism of HTNV-induced CXCL10 production
Spearman correlation analysis showed that the increasing level of CXCL10 was correlated with the increasing BUN (r = 0.345, P < 0.005), Crea (r = 0.138, P < 0.05), and WBC (r = 0.341, P < 0.005) and the decreasing PLT counts (r = −0.500, P < 0.005) in hemorrhagic fever with renal syndrome (HFRS) patients (Figure 1(c))

Summary

Introduction

Hantaan virus (HTNV) is a member of the enveloped Bunyaviridae family characterized by a tripartite single-stranded RNA genome of negative polarity. Inflammatory cytokines/chemokines produced during HTNV infection represent a double-edged sword [5]. On one hand, they contribute to viral elimination by inducing and amplifying innate effectors’ functions and antigen presentation of viral epitopes to T cells. If not properly regulated, inflammatory cytokines/chemokines may facilitate immunopathological processes in HFRS [5]. CXCL10/Interferon-γ-inducible protein-10 (IP-10) is a member of CXC chemokines, which is mainly secreted by endothelial cells, epithelial cells, and keratinocytes. A better understanding of the regulation mechanism of CXCL10 production in infectious diseases might help us develop new therapeutic interventions in human diseases

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Conclusion