Respiratory syncytial virus modifies microRNAs regulating host genes that affect virus replication

Bakre, Abhijeet; Mitchell, Patricia; Coleman, J. Keegan; Jones, Les; Saavedra, Geraldine; Teng, Michael N.; Tompkins, S. Mark; Tripp, Ralph A.

doi:10.1099/vir.0.044255-0

Cited by 80 publications

(108 citation statements)

References 63 publications

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“…39) and CCND1 has also been demonstrated as a predicted target of miR-26b (40). Among our HPV-positive samples, the expression of these two microRNAs was downregulated, which may be an important factor for the high proliferative status of the HPV-positive tumors.…”

Section: Discussionmentioning

confidence: 88%

microRNA Portraits in Human Vulvar Carcinoma

Maia

Lavorato-Rocha

Rodrigues

et al. 2013

Cancer Prevention Research

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Unregulated expression of microRNAs is well known and has already been demonstrated in many tumor types. However, in vulvar carcinoma this field has been unknown territory. Our study characterizes microRNA in vulvar tumors through an expression profile of 754 miRNAs, relating this with clinical and anatomopathologic data, and presence of HPV infection. Twenty HPV-negative and 20 HPV-positive samples, genotyped for high-risk HPVs (HPV16, 18, 31, 33) and a pool of seven normal vulvar skin samples were used for the identification of differentially expressed miRNAs by TLDA Quantitative Real Time PCR (qRT-PCR). Twenty-five differentially expressed microRNAs between HPV-positive and HPV-negative groups and 79 differentially expressed on the tumor compared with normal samples were obtained. A network between microRNA expression profiles and putative target mRNAs predicted by target prediction algorithms and previously demonstrated as relevant in vulvar carcinomas, such as TP53, RB, PTEN, and EGFR was constructed. Downregulation of both miR-223-5p and miR-19-b1-5p were correlated with the presence of lymph node metastasis; downregulation of miR-100-3p and miR-19-b1-5p were correlated with presence of vascular invasion; overexpression of miR-519b and miR-133a were associated with advanced FIGO staging. In conclusion, our study demonstrates that microRNAs may be clinically important in vulvar carcinomas and our findings may help for further studies on functional implications of miRNA deregulation in this type of cancer. Cancer Prev Res; 6(11); 1231-41. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 88%

microRNA Portraits in Human Vulvar Carcinoma

Maia

Lavorato-Rocha

Rodrigues

et al. 2013

Cancer Prevention Research

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“…Specifically, in this study it is shown that the NS1 induces transcription factor KLF6, a positive regulator of TGF-b (Mgbemena et al, 2011), which then suppresses miR-24 in a feedforward pathway that further induces TGF-b. These findings demonstrate a novel mechanism in which RSV NS1 potentially interacts with KLF6 to modulate miR-24 and TGF-b, thus facilitating cell cycle arrest, reduced apoptosis and elevated RSV replication (Bakre et al, 2012;Gibbs et al, 2009;Mgbemena et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…It was hypothesized that miR-24 inhibitor would relieve miR-24 repression of genuine target genes relative to mock-transfected or negative controls as measured by qRT-PCR. A549 cells were transfected with miR-24 inhibitors, or negative controls, for 24 h as described previously (Bakre et al, 2012) and expression levels of the 10 target genes chosen above were measured by qRT-PCR using gene-specific primers relative to 18S rRNA. miR-24 inhibitor transfection increased expression of PLK3, CSNK1G1, FGFR3 and KLF6 (Fig.…”

Section: Mir-24 Repression During Infection Modulates Multiple Cellulmentioning

confidence: 99%

“…Treatment of A549 cells with purified RSV G enhanced let7f expression, a feature not observed following RSV F treatment. Importantly, modulation of the let-7 family of miRNAs with miRNA mimics and inhibitors affected RSV replication, indicating that RSV modulates host miRNA expression to affect the outcome of the antiviral host response and this is mediated to a considerable extent by RSV G protein expression (Bakre et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…miRNA expression is known to be regulated by multiple processes including TLR4 signalling (Nahid et al, 2009(Nahid et al, , 2011aO'Connell et al, 2007;Pauley et al, 2010;Schulte et al, 2013;Taganov et al, 2006), IRF3 activation (Liu et al, 2009), IFN-stimulated gene transcripts (Eis et al, 2005) and by viral proteins such as RSV G (Bakre et al, 2012). RSV infection of A549 cells affects a set of miRNAs (five that are induced and two which are repressed), particularly let-7f expression, which is induced primarily by RSV G (Bakre et al, 2012). Treatment of A549 cells with purified RSV G enhanced let7f expression, a feature not observed following RSV F treatment.…”

Section: Introductionmentioning

confidence: 99%

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Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-β

Bakre

Hiscox

et al. 2015

Journal of General Virology

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Human respiratory syncytial virus (RSV) is a major health challenge in the young and elderly owing to the lack of a safe and effective vaccine and proven antiviral drugs. Understanding the mechanisms by which viral genes and proteins modulate the host response to infection is critical for identifying novel disease intervention strategies. In this study, the RSV non-structural protein NS1 was shown to suppress miR-24 expression during infection. Lack of NS1 was linked to increased expression of miR-24, whilst NS1 overexpression suppressed miR-24 expression. NS1 was found to induce Kruppel-like factor 6 (KLF6), a transcription factor that positively regulates the transforming growth factor (TGF)-b pathway to induce cell cycle arrest. Silencing of KLF6 led to increased miR-24 expression via downregulation of TGF-b. Treatment with exogenous TGF-b suppressed miR-24 expression and induced KLF6. Confocal microscopy showed co-localization of KLF6 and RSV NS1. These findings indicated that RSV NS1 interacts with KLF6 and modulates miR-24 expression and TGF-b, which facilitates RSV replication. Received 23 March 2015Accepted 6 August 2015 INTRODUCTIONHuman respiratory syncytial virus (RSV) is a ubiquitous negative-sense ssRNA virus that can cause severe lung disease following infection (CDC, 2013;Hall et al., 2009;Nair et al., 2010). RSV is a member of the genus Pneumovirus, family Paramyxoviridae with a non-segmented genome that encodes 10 genes and 11 proteins (NS1, NS2, N, P, M, SH, G, F, M2-1, M2-2 and L). The two non-structural proteins (NS1 and NS2), which are not part of the intact virion, are transcribed and translated during infection (Moore et al., 2008).RSV infection rates are high and by age 2 years the majority of young children have experienced at least one infection (CDC, 2008(CDC, , 2013Hall et al., 2009;Mori et al., 2014;Nair et al., 2010;Stockman et al., 2012; Zhou et al., 2012). RSV infection in high-risk individuals, such as infants, young children, immunocompromised adults and the elderly, can manifest as serious pulmonary inflammatory disease including bronchiolitis and pneumonia (Hoffman et al., 2004;Moore et al., 2013;Openshaw & Chiu, 2013;Oshansky et al., 2009b;Psarras et al., 2004;Vicencio, 2010). There is also substantial evidence that early RSV infection can mediate airway remodelling, a feature that predisposes individuals to asthma development and exacerbation (Fong et al., 2000;Foronjy et al., 2014;Hirakawa et al., 2013;Hotard et al., 2015;Liesman et al., 2014;Meng et al., 2014;Piedimonte, 2002Piedimonte, , 2003Tan et al., 2008;Wu et al., 2011). Transforming growth factor (TGF)-b is expressed during RSV infection of lung epithelial cells (Gibbs et al., 2009;McCann & Imani, 2007;Mgbemena et al., 2011) and several studies indicate that it plays an important role in asthma development (de Faria et al., 2008;Fong et al., 2000;Gagliardo et al., 2013;Hoshino et al., 1998;Howell & McAnulty, 2006; Pelaia et al., 2007;Sharma et al., 2009). TGF-b also regulates aspects of the inflammatory cytokine r...

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Respiratory syncytial virus infection inhibits TLR4 signaling via up‐regulation of miR‐26b

Liu

Gao

Wang

et al. 2015

Cell Biology International

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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illnesses in infants worldwide. TLR4 signal pathway plays a critical role in regulating immune response against RSV infection. However, the activation of TLR4 in RSV infection is still unclear. In present study, the expression levels of miR-26b and TLR4 mRNA were detected in peripheral blood mononuclear cells (PBMCs) of children with or without RSV infected bronchiolitis. The expression levels of TLR4 and its downstream genes IFNβ and CCL5 were also quantified in PBMCs infected with RSVΔG or RSV A2 in vitro. The results showed that children with RSV infection had higher miR-26b level and lower TLR4 mRNA level in PBMCs. miR-26b was predicted to target TLR4. In vitro, miR-26b mimic markedly down-regulated TLR4 mRNA/protein expression and IFNβ/CCL5 concentrations while miR-26b inhibitor up-regulated these levels. This study reveals that RSV infection inhibits TLR4 signaling via up-regulation of miR-26b, which provides a potential therapeutic target for preventing and treating RSV infection.

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Respiratory syncytial virus modifies microRNAs regulating host genes that affect virus replication

Cited by 80 publications

References 63 publications

microRNA Portraits in Human Vulvar Carcinoma

microRNA Portraits in Human Vulvar Carcinoma

Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-β

Respiratory syncytial virus infection inhibits TLR4 signaling via up‐regulation of miR‐26b

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