Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: Implications for the hosts’ innate immune response

Kundu, Kiran; Dutta, Kallol; Nazmi, Arshed; Basu, Anirban

doi:10.1016/j.cellimm.2013.09.005

Cited by 40 publications

(38 citation statements)

References 41 publications

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“…JEV has been reported to increase the STAT1 phosphorylation [30]. We observed upregulation in STAT1 phosphorylation (ser727) 12 h post JEV infection (Figure 5A).…”

Section: Resultssupporting

confidence: 54%

“…This suggested that the cellular anti-viral machinery got compromised in miR-146a overexpressing cells and supported viral replication. However, a recent study by Kundu et al reported increased levels of SOCS1 and SOCS3 during early time points of infection which promoted JEV replication at early time points, but the viral titer got decreased due to the decrease in levels of SOCS1 and SOCS3 during later time points, which led to the activated cellular immune response [30]. We also found a decrease in viral mRNA levels at later time points.…”

Section: Discussionsupporting

confidence: 42%

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

Sharma

Verma

Kumawat

et al. 2015

J Neuroinflammation

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BackgroundJapanese encephalitis virus (JEV) is the causative agent of Japanese encephalitis which is more prevalent in South and Southeast Asia. JEV is a neurotropic virus which infiltrates into the brain through vascular endothelial cells. JEV infects neurons and microglial cells which causes neuronal damage and inflammation. However, JEV also evades the cellular immune response to survive in host cells. Viruses are known to modulate the expression of microRNAs, which in turn modulate cellular immune response by targeting expression of antiviral genes. The aim of this study is to understand the anti-inflammatory role of miR-146a during JEV infection, which facilitates immune evasion.MethodsHuman brain microglial cells (CHME3) were infected by JEV: JaOArS982 and P20778 strain, and expression of miR-146a were analyzed. Overexpression and knockdown studies of miR-146a were done to see the effect on NF-κB pathway and antiviral Jak-STAT pathway. Regulatory role of miR-146a on expression of interferon-stimulated genes was determined by real-time PCR and luciferase assays.ResultsJEV infection elevated the expression of miR-146a in JaOArS982 strain which caused downregulation of TRAF6, IRAK1, IRAK2, and STAT1 genes. Exogenous overexpression of miR-146a led to suppression of NF-κB activation and abrogation of Jak-STAT pathway upon JEV infection which led to downregulation of interferon-stimulated genes (IFIT-1 and IFIT-2) and facilitated viral replication. JEV infection initially upregulated cytokine production and activated STAT1 activity but STAT1 levels reduced at later time point, which led to the downregulation of interferon-stimulated genes.ConclusionUpregulation of miR-146a by JEV JaOArS982 strain leads to suppression of NF-κB activity and disruption of antiviral Jak-STAT signaling which helps the virus to evade the cellular immune response. This effect of JEV infection on miR-146a expression was found to be strain specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0249-0) contains supplementary material, which is available to authorized users.

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“…JEV has been reported to increase the STAT1 phosphorylation [30]. We observed upregulation in STAT1 phosphorylation (ser727) 12 h post JEV infection (Figure 5A).…”

Section: Resultssupporting

confidence: 54%

Section: Discussionsupporting

confidence: 42%

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

Sharma

Verma

Kumawat

et al. 2015

J Neuroinflammation

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110

100

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“…Specifically, the focus was placed on three negative IFN regulators that have been shown to be relevant in the context of herpesvirus and other viral infections. SOCS1 is an IFN-inducible Jak kinase inhibitor that suppresses both type I and type II IFN signaling in the context of multiple virus infections (Kundu, Dutta et al, 2013; Shao, Zhang et al, 2013; Charoenthongtrakul, Zhou et al, 2011; Frey, Ahmed et al, 2009). PIAS1 is a SUMO ligase that facilitates viral replication by inhibiting activated Stat1 and IRF-3; it may have additional proviral roles during EBV and HCMV replication (Chang, Lee et al, 2004; Liu, Mink et al, 2004; Lee, Kang et al, 2003; Li, Pan et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

et al. 2017

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Ataxia-Telangiectasia mutated (ATM) kinase participates in multiple networks, including DNA damage response, oxidative stress, and mitophagy. ATM also supports replication of diverse DNA and RNA viruses. Gammaherpesviruses are prevalent cancer-associated viruses that benefit from ATM expression during replication. This proviral role of ATM had been ascribed to its signaling within the DNA damage response network; other functions of ATM have not been considered. In this study increased type I interferon (IFN) responses were observed in ATM deficient gammaherpesvirus-infected macrophages. Using a mouse model that combines ATM and type I IFN receptor deficiencies we show that increased type I IFN response in the absence of ATM fully accounts for the proviral role of ATM during gammaherpesvirus replication. Further, increased type I IFN response rendered ATM deficient macrophages more susceptible to antiviral effects of type II IFN. This study identifies attenuation of type I IFN responses as the primary mechanism underlying proviral function of ATM during gammaherpesvirus infection.

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“…RSV non-structural proteins have been reported to induce the expression of SOCS1 and SOCS3 proteins ultimately leading to the suppression of IFN signaling28. Kundu et al 29. has reported the upregulation of SOCS1 and SOCS3 in JEV infected mouse macrophages29.…”

Section: Discussionmentioning

confidence: 99%

Japanese Encephalitis Virus exploits the microRNA-432 to regulate the expression of Suppressor of Cytokine Signaling (SOCS) 5

Sharma

Kumawat

Rastogi

et al. 2016

Sci Rep

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Japanese encephalitis virus (JEV) is a plus strand RNA virus, which infects brain. MicroRNAs are regulatory non-coding RNAs which regulate the expression of various genes in cells. Viruses modulate the expression of various microRNAs to suppress anti-viral signaling and evade the immune response. SOCS (Suppressor of cytokine signalling) family of proteins are negative regulators of anti-viral Jak-STAT pathway. In this study, we demonstrated the regulatory role of SOCS5 in Jak-STAT signaling and its exploitation by JEV through a microRNA mediated mechanism. JEV infection in human brain microglial cells (CHME3) downregulated the expression of miR-432, and upregulated SOCS5 levels. SOCS5 was validated as a target of miR-432 by using 3′UTR clone of SOCS5 in luciferase vector along with miR-432 mimic. The overexpression of miR-432 prior to JEV infection enhanced the phosphorylation of STAT1 resulting into increased ISRE activity and cellular inflammatory response resulting into diminished viral replication. The knockdown of SOCS5 resulted into increased STAT1 phosphorylation and suppressed viral replication. JEV infection mediated downregulation of miR-432 leads to SOCS5 upregulation, which helps the virus to evade cellular anti-viral response. This study demonstrated that JEV utilizes this microRNA mediated strategy to manipulate cellular immune response promoting JEV pathogenesis.

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Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: Implications for the hosts’ innate immune response

Cited by 40 publications

References 41 publications

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

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

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

Japanese Encephalitis Virus exploits the microRNA-432 to regulate the expression of Suppressor of Cytokine Signaling (SOCS) 5

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