Abstract
Dengue Virus (DENV) infection can cause severe illness such as highly fatality dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Innate immune activation by Nod-like receptors (NLRs) is a critical part of host defense against viral infection. Here, we revealed a key mechanism of NLRP12-mediated regulation in DENV infection. Firstly, NLRP12 expression was inhibited in human macrophage following DENV or other flaviviruses (JEV, YFV, ZIKV) infection. Positive regulatory domain 1 (PRDM1) was induced by DENV or poly(I:C) and suppressed NLRP12 expression, which was dependent on TBK-1/IRF3 and NF-κB signaling pathways. Moreover, NLRP12 inhibited DENV and other flaviviruses (JEV, YFV, ZIKV) replication, which relied on the well-conserved nucleotide binding structures of its NACHT domain. Furthermore, NLRP12 could interact with heat shock protein 90 (HSP90) dependent on its Walker A and Walker B sites. In addition, NLRP12 enhanced the production of type I IFNs (IFN-α/β) and interferon-stimulated genes (ISGs), including IFITM3, TRAIL and Viperin. Inhibition of HSP90 with 17-DMAG impaired the upregulation of type I IFNs and ISGs induced by NLRP12. Taken together, we demonstrated a novel mechanism that NLRP12 exerted anti-viral properties in DENV and other flaviviruses (JEV, YFV, ZIKV) infection, which brings up a potential target for the treatment of DENV infection.
Highlights
Flaviviruses are a group of enveloped viruses with positive-sense, single-stranded RNA genomes [1]
To investigate the impact of flaviviruses infection on expression of Nod-like receptors (NLRs), human monocyte-derived macrophages (hMDMs) were infected with Dengue Virus (DENV), and NLRs mRNA levels were detected by qPCR
Data showed that DENV infection dramatically reduced the expression of NOD-like receptor 12 (NLRP12) (Figure 1A), while no differences were observed in NLRP2, NLRP4, NLRP7 and NLRP10 expression
Summary
Flaviviruses are a group of enveloped viruses with positive-sense, single-stranded RNA genomes [1] Common flavivirus genus, such as Dengue virus (DENV), Zika virus (ZIKV), Japanese Encephalitis virus (JEV) and Yellow Fever virus (YFV), were widely spread in the global population and caused substantial morbidity each year [2]. DENV is widespread in various geographical locations, isolation treatment and symptomatic supportive treatment are considered as the major treatment methods, and no specific treatments are available to date [2]. It is a desperate need for improved understanding of the immunological mechanisms driving DENV infection and developing new therapies
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