Inhibition of IL-2 inducible T-cell kinase alleviates T-cell activation and murine myocardial inflammation associated with CVB3 infection

He, Feng; Yao, Hailan; Xiao, Zhengguo; Han, Jiahong; Zou, Jizhen; Liu, Zhewei

doi:10.1016/j.molimm.2013.12.004

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…One half of the heart was weighed and homogenized in 0.5 ml of MEM and centrifuged for 10 min at 800 ϫ g/min; infectious virus titers in the supernatants were then analyzed by the viral plaque assay, and the virus titers in infected tissue were expressed as PFU/g. The other half of the heart was examined histopathologically for evidence of inflammation and necrosis, as previously described (14,17). Neutralization assays were performed as previously described by Barnes et al (7) on sera collected from mice 1 month after i.p.…”

Section: Methodsmentioning

confidence: 99%

Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice

Yao

Wang

et al. 2015

J Virol

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Coxsackievirus B3 (CVB3) is trophic for cardiac tissue and is a major causative agent for viral myocarditis, where local viral replication in the heart may lead to heart failure or even death. Recent studies show that inserting microRNA target sequences into the genomes of certain viruses can eradicate these viruses within local host tissues that specifically express the cognate microRNA. Here, we demonstrated both in vitro and in vivo that incorporating target sequences for miRNA-133 and -206 into the 5= untranslated region of the CVB3 genome ameliorated CVB3 virulence in skeletal muscle and myocardial cells that specifically expressed the cognate cellular microRNAs. Compared to wild-type CVB3, viral replication of the engineered CVB3 was attenuated in human TE671 (rhabdomyosarcoma) and L6 (skeletal muscle) cell lines in vitro that expressed high levels of miRNA-206. In the in vivo murine CVB3-infection model, viral replication of the engineered CVB3 was attenuated specifically in the heart that expressed high levels of both miRNAs, but not in certain tissues, which allowed the host to retain the ability to induce a strong and protective humoral immune response against CVB3. The results of this study suggest that a microRNA-targeting strategy to control CVB3 tissue tropism and pathogenesis may be useful for viral attenuation and vaccine development. IMPORTANCECoxsackievirus B3 (CVB3) is a major causative agent for viral myocarditis, and viral replication in the heart may lead to heart failure or even death. Limiting CVB3 replication within the heart may be a promising strategy to decrease CVB3 pathogenicity. miRNAs are ϳ21-nucleotide-long, tissue-specific endogenous small RNA molecules that posttranscriptionally regulate gene expression by imperfectly binding to the 3= untranslated region (UTR), the 5= UTR, or the coding region within a gene. In our study, muscle-specific miRNA targets (miRT) were incorporated into the CVB3 genome. Replication of the engineered viruses was restricted in the important heart tissue of infected mice, which reduced cardiac pathology and increased mouse survival. Meanwhile, replication ability was retained in other tissues, thus inducing a strong humoral immune response and providing long-term protection against CVB3 rechallenge. This study suggests that a microRNA-targeting strategy can potentially control CVB3 tissue tropism and pathogenesis and may be useful for viral attenuation and vaccine development. C oxsackievirus B3 (CVB3) is a clinically relevant infectious agent that causes viral myocarditis, pancreatitis, and aseptic meningitis. CVB3 is cardiotropic and efficiently replicates in the heart. We and others have shown in various animal models that CVB3 replication induces a direct cytopathic effect on infected cells, leading to tissue damage (1, 2). At present, there is no effective therapy against CVB3, and strategies to develop such a therapy are greatly desired (3, 4). Limiting CVB3 replication within the heart may be a promising strategy to decrease CVB3 pathoge...

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Section: Methodsmentioning

confidence: 99%

Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice

Yao

Wang

et al. 2015

J Virol

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“…Coxsackievirus B3 (CVB3) is a common and important pathogen of viral myocarditis, pancreatitis, and aseptic meningitis in young children and infants. CVB3 infection may lead to acute heart failure and sudden death due to direct cytopathic effects induced by viral replication in the early phase of infection [1, 2]. Virus elimination from vital organs is considered as a key therapeutic strategy to treat CVB3-associated diseases.…”

Section: Introductionmentioning

confidence: 99%

The protective role of microRNA-21 against coxsackievirus B3 infection through targeting the MAP2K3/P38 MAPK signaling pathway

Xiao

Yao

et al. 2019

J Transl Med

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Background The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. We previously demonstrated microRNA-21 has potential inhibitory effect on the MAP2K3 which locates upstream of P38 MAPK and was upregulated in mouse hearts upon CVB3 infection. However, the effect and underlying mechanism of miRNA-21 on CVB3 infection remain unclear. Methods We detected continuous changes of cellular miRNA-21 and P38 MAPK proteins expression profiling post CVB3 infection in vitro within 12 h. P38 MAPK signaling was inhibited by the specific inhibitor, small interfering RNA and miRNA-21 mimic in vitro, CVB3 replication, cell apoptosis rate and proliferation were detected. Viral load in the mice heart, cardiomyocyte apoptosis rate and histological of the heart were also detected in the mice model of viral myocarditis pretreated with miRNA-21-lentivirus. Results We observed significant upregulation of miRNA-21 expression followed by suppression of the MAP2K3/P38 MAPK signaling in CVB3-infected Hela cells. The inactivation of the MAP2K3/P38 MAPK signaling by P38 MAPK specific inhibitor, small interfering RNA against MAP2K3, or miRNA-21 overexpression significantly inhibited viral progeny release from CVB3-infected cells. Mechanistically, when compared with control miRNA, miRNA-21 showed no effect on capsid protein VP1 expression and viral load within host cells, while significantly reversing CVB3-induced caspase-3 activation and cell apoptosis rate, further promoting proliferation of infected cells, which indicates the inhibitory effect of miRNA-21 on CVB3 progeny release. In the in vivo study, when compared with control miRNA, miRNA-21 pretreatment remarkably inactivated the MAP2K3/P38 MAPK signaling in mice and protected them against CVB3 infection as evidenced by significantly alleviated cell apoptosis rate, reduced viral titers, necrosis in the heart as well as by remarkably prolonged survival time. Conclusions miRNA-21 were reverse correlated with P38 MAPK activation post CVB3 infection, miRNA-21 overexpression significantly inhibited viral progeny release and decreased myocytes apoptosis rate in vitro and in vivo, suggesting that miRNA-21 may serve as a potential therapeutic agent against CVB3 infection through targeting the MAP2K3/P38 MAPK signaling.

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“…Increasing evidence has shown that indirect immune-mediated injury, but not direct virus-induced damage, is the prominent pathological mechanism of CVB3-induced myocarditis 12 13 . Two genders display diverse immune patterns, strength as well as immune modulations in the disease process of viral myocarditis 14 15 .…”

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confidence: 99%

Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4+IL-10+ T cells

Yan

Xiong

2016

Sci Rep

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Coxsackievirus group B type 3 (CVB3) is a common etiologic agent of viral myocarditis and often causes sexually dimorphic myocarditis with increased incidence and mortality in male. So far, the underlying mechanism for the high male prevalence is not well elucidated. In this study, we deciphered the role of myeloid-derived suppressor cells (MDSCs) in the gender bias in murine CVB3-induced myocarditis by comparing their frequencies, subsets as well as immune suppressive functions. We found that much more myocardial MDSCs were enriched in infected females than males, with dramatically higher percentage ratio of CD11b+Ly6G-Ly6Chigh monocytic subset (M-MDSCs) to CD11b+Ly6G+Ly6Clow granulocytic subset (G-MDSCs). Interestingly, more potent suppression on T cell proliferation was also evidenced in female-derived M-MDSCs. Consistently, adoptive transfer of female- but not male-derived M-MDSCs efficiently alleviated CVB3-induced myocarditis in male recipient mice, and this protection could be ascribed to the increased induction of regulatory and CD4+IL-10+ T cells. Our study suggested that myocardial MDSCs were distinctively induced not only in quantities but also in phenotypes and immune suppressive functions in CVB3-infected males and females; and female-derived more suppressive M-MDSCs contributed to their insensitivity to CVB3-induced myocarditis.

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Inhibition of IL-2 inducible T-cell kinase alleviates T-cell activation and murine myocardial inflammation associated with CVB3 infection

Cited by 10 publications

References 33 publications

Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice

Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice

The protective role of microRNA-21 against coxsackievirus B3 infection through targeting the MAP2K3/P38 MAPK signaling pathway

Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4+IL-10+ T cells

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