A Chimeric A2 Strain of Respiratory Syncytial Virus (RSV) with the Fusion Protein of RSV Strain Line 19 Exhibits Enhanced Viral Load, Mucus, and Airway Dysfunction

Moore, Martin L.; Alp, Michael H.; Luongo, Cindy; Lukacs, Nicholas W.; Polosukhin, Vasiliy V.; Huckabee, M.M.; Newcomb, Dawn C.; Buchholz, Ursula J.; Crowe, James E.; Goleniewska, Kasia; Williams, John V.; Collins, Peter L.; Peebles, R. Stokes

doi:10.1128/jvi.01853-08

Cited by 152 publications

(246 citation statements)

References 61 publications

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“…Recently established, this mouse model using the recRSV A2-L19F strain exhibits higher lung viral loads, more airway mucus, and more severe respiratory distress than both the parental A2 and line 19 strains (38,42), recapitulating key clinical parameters of infant RSV bronchiolitis (38,40,55). Although it is not determined yet whether pathogenicity of a resistant RSV-F D401E would be equally unchanged in the human host, efficient replication in particular of this recombinant in the mouse model raises concern that resistance mutations in the hotspot around F residue 400 could become prevalent in circulating RSV strains should any of these entry inhibitor classes experience broad clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…The induction of extensive mucus production is one of the key features associated with RSV pathogenesis (41) and serves as an indicator for the severity of RSV disease in the mouse model (38,42). When we infected animals with the two mutant recombinants and standard recRSV, the recRSV A2-L9F D489E mutant was only slightly mucogenic compared with mock-infected mice (Fig.…”

Section: A Previously Unidentified Chemical Class Of Small-molecule Rmentioning

confidence: 99%

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Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Yan

Lee

Thakkar

et al. 2014

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

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109

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Respiratory syncytial virus (RSV) is a leading pediatric pathogen that is responsible for a majority of infant hospitalizations due to viral disease. Despite its clinical importance, no vaccine prophylaxis against RSV disease or effective antiviral therapeutic is available. In this study, we established a robust high-throughput drug screening protocol by using a recombinant RSV reporter virus to expand the pool of RSV inhibitor candidates. Mechanistic characterization revealed that a potent newly identified inhibitor class blocks viral entry through specific targeting of the RSV fusion (F) protein. Resistance against this class was induced and revealed overlapping hotspots with diverse, previously identified RSV entry blockers at different stages of preclinical and clinical development. A structural and biochemical assessment of the mechanism of unique, broad RSV cross-resistance against structurally distinct entry inhibitors demonstrated that individual escape hotspots are located in immediate physical proximity in the metastable conformation of RSV F and that the resistance mutations lower the barrier for prefusion F triggering, resulting in an accelerated RSV entry kinetics. One resistant RSV recombinant remained fully pathogenic in a mouse model of RSV infection. By identifying molecular determinants governing the RSV entry machinery, this study spotlights a molecular mechanism of broad RSV resistance against entry inhibition that may affect the impact of diverse viral entry inhibitors presently considered for clinical use and outlines a proactive design for future RSV drug discovery campaigns.antiviral drugs | drug resistance

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Section: Discussionmentioning

confidence: 99%

Section: A Previously Unidentified Chemical Class Of Small-molecule Rmentioning

confidence: 99%

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Yan

Lee

Thakkar

et al. 2014

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

Self Cite

109

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“…Studies are ongoing to determine which amino acids in the F protein regulate these immunologic and physiologic parameters. (Moore et al, 2009) Mice infected with different low passage clinical isolates also may have pathologic sequelae similar to those seen with line 19 and A2 infection. (Stokes et al, 2011) Nasal secretions obtained from children presenting to the Vanderbilt Vaccine Clinic with RSV group A infection were used to infect HEp-2 cells.…”

Section: Primary Infection In Micementioning

confidence: 99%

Challenges and Opportunities for Respiratory Syncytial Virus Vaccines

2013

Current Topics in Microbiology and Immunology

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Reactive airway disease (RAD) is a general term for respiratory illnesses manifested by wheezing. Respiratory syncytial virus (RSV) results in wheezing, either by causing bronchiolitis or by inducing acute exacerbations of asthma. There has been a long standing interest in whether severe RSV bronchiolitis in infancy is a risk factor for the development of asthma later in childhood. While epidemiologic studies have suggested that such a link exists, a very recent study suggests that infants with greater airways responsiveness to methacholine instead have an increased prevalence of severe RSV bronchiolitis. Increased airways responsiveness to methacholine has been implicated as a key factor for loss of lung function in asthmatic subjects, suggesting that instead of being causal, severe RSV infection may instead be a marker of a predisposing factor for asthma. In this chapter, we will explore the evidence that RSV infection leads to RAD in infants and adults, and how these different forms of RAD may be linked.

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“…In autopsy lung tissues from fatal HRSV disease cases, epithelial damage and mechanical airway obstruction are implicated as key features of HRSV pathogenesis (Johnson et al, 2007;Welliver et al, 2007). Although laboratory animal models of HRSV pathogenesis have been widely used to determine pathogenic mechanisms of HRSV infection, the commonly used lab strains of HRSV do not cause airway epithelial cell desquamation, airway mucus production, or lung dysfunction in mice (Moore et al, 2009a;Peebles et al, 2001). However, some strains of HRSV (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…However, some strains of HRSV (e.g. line 19 and clinical isolate A2001/2-20) were shown to cause airway mucus expression and lung dysfunction in mice, and clinical isolates can cause airway epithelial cell desquamation in mice (Moore et al, 2009a;Stokes et al, 2011). The fusion (F) glycoprotein of HRSV strain line 19 was implicated in the mechanism of line 19-induced airway mucus (Moore et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

Animal Models of Respiratory Syncytial Virus Pathogenesis and Vaccine Development: Opportunities and Future Directions

Woolums¹,

Moore²

2011

Human Respiratory Syncytial Virus Infection

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A Chimeric A2 Strain of Respiratory Syncytial Virus (RSV) with the Fusion Protein of RSV Strain Line 19 Exhibits Enhanced Viral Load, Mucus, and Airway Dysfunction

Abstract: Respiratory syncytial virus (RSV) is

Cited by 152 publications

References 61 publications

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Challenges and Opportunities for Respiratory Syncytial Virus Vaccines

Animal Models of Respiratory Syncytial Virus Pathogenesis and Vaccine Development: Opportunities and Future Directions

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