Regulatory role of TRIM21 in the type-I interferon pathway in Japanese encephalitis virus-infected human microglial cells

Abstract

BackgroundJapanese encephalitis virus (JEV) infection leads to Japanese encephalitis (JE) in humans. JEV is transmitted through mosquitoes and maintained in a zoonotic cycle. This cycle involves pigs as the major reservoir, water birds as carriers and mosquitoes as vectors. JEV invasion into the central nervous system (CNS) may occur via antipodal transport of virions or through the vascular endothelial cells. Microglial cells get activated in response to pathogenic insults. JEV infection induces the innate immune response and triggers the production of type I interferons. The signaling pathway of type I interferon production is regulated by a number of molecules. TRIM proteins are known to regulate the expression of interferons; however, the involvement of TRIM genes and their underlying mechanism during JEV infection are not known.MethodsHuman microglial cells (CHME3) were infected with JEV to understand the role of TRIM21 in JEV infection and its effect on type I interferon (IFN-β) production. Cells were infected in presence and absence of exogenous TRIM21 as well as after knocking down the TRIM21 mRNA. Levels of activated IRF3 expression were measured through Western blot analyses of anti-p-IRF3 antibody, and IFN-β production was measured by using IFN-β real-time PCR and luciferase activity analyses.ResultsJEV infection increased expression of TRIM21 in CHME3 cells. JEV induced an innate immune response by increasing production of IFN-β via IRF3 activation and phosphorylation. Overexpression of TRIM21 resulted in downregulation of p-IRF3 and IFN-β, while silencing led to increased production of p-IRF3 and IFN-β in JEV-infected CHME3 cells.ConclusionThis report demonstrates TRIM21 as a negative regulator of interferon-β (IFN-β) production mediated by IRF-3 during JEV infection in human microglial cells.

miR-146a suppresses cellular immune response during Japanese encephalitis virus JaOArS982 strain infection in human microglial cells

“…However, the survivors still show neurological and cognitive impairments [31]. JEV has been reported to evade the innate response of host and establish pathogenesis [32].…”

Amelioration of Japanese encephalitis by blockage of 4-1BB signaling is coupled to divergent enhancement of type I/II IFN responses and Ly-6Chi monocyte differentiation

“…Myeloid cells, including both tissue and lymphoid DCs and macrophages, are primary target cells for JEV infection and regulate the spread of a virus to distant tissues such as the CNS [7,8]. In addition, myeloid cells can produce IFN-I proteins (IFN-α/β) via PRR recognition upon JEV infection, which plays a crucial role in controlling viral replication at the periphery [16][17][18][19][20]. Because virus load at the periphery of 4-1BB KO mice was lower than that of wild-type BL/6 mice in the present study, we assessed whether 4-1BB signaling would affect JEV replication and IFN-I innate response in myeloidderived cells as primary target cells, in order to further define the role of 4-1BB signaling in controlling JE progression.…”

“…While JEV-specific T cells and virus-neutralizing IgM and IgG are considered to participate in the clearance of virus from both peripheral lymphoid tissues and the CNS [11], innate immune responses appear to play a more crucial role in the early control of JEV infection, due to delayed establishment of adaptive immunity. The type I IFN (IFN-I; typically IFN-α/β) innate immune response is essential for controlling various viral infections, including JEV [12][13][14][15], and IFN-I production is triggered by recognition of viral pathogen-associated molecular patterns (PAMPs) through cytoplasmic helicases (RIG-I, MDA5) and Toll-like receptors (TLRs) [16][17][18][19][20]. In addition, recent data indicate that type II IFN (IFN-II; only member IFNγ) produced by NK and CD4 + Th1 cells has a beneficial effect on disease outcomes after JEV infection [21,22], although the requirement for IFN-II in recovery from infection with different flaviviruses varies [21,[23][24][25][26][27][28][29].…”

TRIM32 promotes cell proliferation and invasion by activating β‐catenin signalling in gastric cancer

“…TRIM family proteins participate in a wide range of biological processes, such as cell growth, migration, differentiation, apoptosis, and immunity 5, 6, 7, 8. In the past few years, the role of TRIM proteins received much attention regarding innate immunity to viral infections 9. Recently, researchers found that TRIM proteins also serve as oncogenes or tumour suppressors implicated in various cancers, including GC.…”