Respiratory Syncytial Virus Proteins Modulate Suppressors of Cytokine Signaling 1 and 3 and the Type I Interferon Response to Infection by a Toll-Like Receptor Pathway

Oshansky, Christine M.; Krunkosky, Thomas M.; Barber, James P.; Jones, Les; Tripp, Ralph A.

doi:10.1089/vim.2008.0098

Cited by 70 publications

(79 citation statements)

References 75 publications

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“…Of interest, mutations in TLR4 that reduce receptor activity were overrepresented in infants hospitalized with RSV (33). On the other hand, RSV-G glycoprotein modulates suppressor of cytokine signaling family of proteins (SOCS) expression that negatively regulates cytokine expression and results in inhibition of type 1 IFN and IFN-stimulated gene-15 expression (34). Targeting the G glycoprotein, as in this study, resulted in reduction of AHR and airway inflammation.…”

Section: Cx3cr1mentioning

confidence: 59%

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

Han

Takeda

Wang

et al. 2014

Am J Respir Cell Mol Biol

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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illnesses in infants worldwide. Both RSV-G and RSV-F glycoproteins play pathogenic roles during infection with RSV. The objective of this study was to compare the effects of anti-RSV-G and anti-RSV-F monoclonal antibodies (mAbs) on airway hyperresponsiveness (AHR) and inflammation after primary or secondary RSV infection in mice. In the primary infection model, mice were infected with RSV at 6 weeks of age. Anti-RSV-G or anti-RSV-F mAbs were administered 24 hours before infection or Day 12 postinfection. In a secondary infection model, mice were infected (primary) with RSV at 1 week (neonate) and reinfected (secondary) 5 weeks later. Anti-RSV-G and anti-RSV-F mAbs were administered 24 hours before the primary infection. Both mAbs had comparable effects in preventing airway responses after primary RSV infection. When given 2 days after infection, anti-RSV-G-treated mice showed significantly decreased AHR and airway inflammation, which persisted in anti-RSV-F-treated mice. In the reinfection model, anti-RSV-G but not anti-RSV-F administered during primary RSV infection in neonates resulted in decreased AHR, eosinophilia, and IL-13 but increased levels of IFN-g in bronchoalveolar lavage on reinfection. These results support the use of anti-RSV-G in the prevention and treatment of RSV-induced disease.

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Section: Cx3cr1mentioning

confidence: 59%

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

Han

Takeda

Wang

et al. 2014

Am J Respir Cell Mol Biol

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“…In this regard, the recent advent of technology to culture primary human airway epithelial cells into physiologically authentic pseudostratified airway epithelial (HAE) cultures is very attractive (16). Indeed, such cultures already have been used to study a number of respiratory virus-host interactions, including RSV (17)(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

Villenave

Thavagnanam

Sarlang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

166

217

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Respiratory syncytial virus (RSV) is the major viral cause of severe pulmonary disease in young infants worldwide. However, the mechanisms by which RSV causes disease in humans remain poorly understood. To help bridge this gap, we developed an ex vivo/in vitro model of RSV infection based on well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs), the primary targets of RSV infection in vivo. Our RSV/WD-PBEC model demonstrated remarkable similarities to hallmarks of RSV infection in infant lungs. These hallmarks included restriction of infection to noncontiguous or small clumps of apical ciliated and occasional nonciliated epithelial cells, apoptosis and sloughing of apical epithelial cells, occasional syncytium formation, goblet cell hyperplasia/metaplasia, and mucus hypersecretion. RSV was shed exclusively from the apical surface at titers consistent with those in airway aspirates from hospitalized infants. Furthermore, secretion of proinflammatory chemokines such as CXCL10, CCL5, IL-6, and CXCL8 reflected those chemokines present in airway aspirates. Interestingly, a recent RSV clinical isolate induced more cytopathogenesis than the prototypic A2 strain. Our findings indicate that this RSV/WD-PBEC model provides an authentic surrogate for RSV infection of airway epithelium in vivo. As such, this model may provide insights into RSV pathogenesis in humans that ultimately lead to successful RSV vaccines or therapeutics.

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“…A549 cells (ATCC CCL-185) were cultured in Dulbecco's modified Eagle's medium (DMEM) (HyClone) containing 5% heatinactivated FBS (Hyclone) (Bakre et al, 2012;Oshansky et al, 2009a). Mycoplasma-free stocks of RSV strain A2 and those lacking the NS1 or NS2 genes (rA2DNS1EGFP or rA2DNS2EGFP, respectively) (Webster Marketon et al, 2014) were expanded in Vero E6 cells (ATCC CCL-81) and maintained in DMEM (Hyclone) supplemented with 5% heatinactivated FBS (Hyclone) as described previously (Bakre et al, 2012;Oshansky et al, 2009a). Recombinant TGF-b (Peprotech) was reconstituted in 10 mM citric acid buffer as per the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Codon deoptimized RSV is attenuated in vitro, but evokes a strong humoral response upon vaccination and challenge (Meng et al, 2014). These and other immune modulators inhibit the development of the antiviral state (Bossert et al, 2003;Elliott et al, 2007;Goswami et al, 2013;Lo et al, 2005;Moore et al, 2008;Oshansky et al, 2009a;Spann et al, 2005).The role of microRNAs (miRNAs) in post-transcriptional regulation of host genes responding to RSV infection is not fully understood. miRNA expression is known to be regulated by multiple processes including TLR4 signalling (Nahid et al, 2009(Nahid et al, , 2011a O'Connell et al, 2007;Pauley et al, 2010;Schulte et al, 2013;Taganov et al, 2006) …”

mentioning

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 Proteins Modulate Suppressors of Cytokine Signaling 1 and 3 and the Type I Interferon Response to Infection by a Toll-Like Receptor Pathway

Cited by 70 publications

References 75 publications

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

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

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