Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33

Saravia, Jordy; You, Dahui; Shrestha, Bishwas; Jaligama, Sridhar; Siefker, David; Lee, Greg I.; Harding, Jeffrey N; Jones, Tamekia L.; Rovnaghi, Cynthia R.; Bagga, Bindiya; DeVincenzo, John P.; Cormier, Stephania A.

doi:10.1371/journal.ppat.1005217

Cited by 149 publications

(197 citation statements)

References 53 publications

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“…There is a large body of support for IL-13 as an independent and "pivotal" cytokine in the genesis of asthma (reviewed in reference 182). IL-33 may be involved in asthma genesis (183) and not just asthma exacerbation as with other models of infection, such as rhinovirus-induced asthma exacerbations that have been reported (41) (Fig. 4).…”

Section: A Causal Link Between Rsv Infection and Asthmamentioning

confidence: 85%

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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SUMMARY Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.

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Section: A Causal Link Between Rsv Infection and Asthmamentioning

confidence: 85%

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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“…Furthermore, IL-33 and ILC2s are required for the immunopathophysiology typically observed in allergic asthma, a disease phenotypically similar to severe RSV in human infants. Interestingly, neonatal mice have higher percentages of pulmonary ILC2s than adult mice do (7). These data demonstrate a mechanistic role for epitheliumderived IL-33 in RSV immunopathogenesis and suggest that IL-33-mediated ILC2 responses are significant drivers of the Th2 immune response.…”

Section: Ilc2smentioning

confidence: 72%

“…During infection, the airway epithelium is a major source of the "alarmin" cytokine interleukin-33 (IL-33). Intriguingly, nasal aspirates from infants with severe RSV disease have elevated levels of IL-33 (7,8), and variants of the IL-33 receptor gene IL1RL1 are associated with severe RSV disease in human infants (9). Immediately following RSV infection in neonatal mice, a robust IL-33 response is elicited in CD45…”

Section: Epithelial Cellsmentioning

confidence: 99%

Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

You

Saravia

Siefker

et al. 2016

J Virol

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The infant immune response to respiratory syncytial virus (RSV) remains incompletely understood. Here we review the use of a neonatal mouse model of RSV infection to mimic severe infection in human infants. We describe numerous age-specific responses, organized by cell type, observed in RSV-infected neonatal mice and draw comparisons (when possible) to human infants. R espiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants, and severe RSV disease during infancy is associated with an increased risk of asthma development. The medical and economic burdens of RSV infection are enormous. In the United States alone, there are 85,000 to 144,000 annual hospitalizations with $2.6 billion in associated estimated medical cost (1). Despite its continued impact on global health, RSV remains without a vaccine or adequate therapeutic.While prematurity, immunodeficiency, and congenital heart or chronic lung diseases are risk factors for severe RSV disease, the majority of the infants requiring hospitalization were previously healthy and less than 6 months of age (2), suggesting that age at the time of initial infection is an important predictive factor for disease severity. Therefore, our grasp of severe RSV disease in infants is inevitably tied to our understanding of developmental immunity during the first year of life.The neonatal mouse model of RSV infection has been an invaluable tool for RSV research (3, 4). Briefly, neonatal mice (Յ7 days of age) are infected with RSV and then reinfected 4 weeks later as adults. Compared to mice initially infected as adults, these mice develop the characteristic Th2-biased immunopathologies, including exaggerated pulmonary Th2 cells/cytokines, eosinophilia, mucus hyperproduction, and airway hyperreactivity. In recent years, this model spurred several significant advances in research on how age-dependent differences in various immune and nonimmune cells initiate the immunopathogenesis of RSV infection in infants. This article will briefly discuss said advances, organized by the cell types involved in responding to RSV. EPITHELIAL CELLSThe major cellular target of RSV is airway epithelial cells. In the lower respiratory tract, RSV infects bronchiolar and alveolar (type I and II) epithelial cells (5) and similar cells in mice (6). During infection, the airway epithelium is a major source of the "alarmin" cytokine interleukin-33 (IL-33). Intriguingly, nasal aspirates from infants with severe RSV disease have elevated levels of 8), and variants of the IL-33 receptor gene IL1RL1 are associated with severe RSV disease in human infants (9). Immediately following RSV infection in neonatal mice, a robust IL-33 response is elicited in CD45 Ϫ EpCam ϩ pneumocytes (7); this type of response to RSV infection does not occur in adult mice, suggesting age-dependent regulation of IL-33 expression in the lung. Furthermore, the severity of RSV infection (i.e., Th2-mediated immunopathology) is dependent on the levels of IL-33 early during infection. ILC2SMor...

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“…8,58 In respiratory syncytial virus (RSV) infections, ILC2s can confer a type 2-cytokine-associated disease. 59 In humans, ILC2s have not been described directly in these pathologies. However, IL-33 and IL-25 have been detected in nasal fluids of infants hospitalized with RSV bronchiolitis 59 and in asthmatic subjects following experimental rhinovirus (RV)16-infection.…”

Section: Viral Infections and Exacerbationsmentioning

confidence: 99%

“…59 In humans, ILC2s have not been described directly in these pathologies. However, IL-33 and IL-25 have been detected in nasal fluids of infants hospitalized with RSV bronchiolitis 59 and in asthmatic subjects following experimental rhinovirus (RV)16-infection. 60,61 The supernatant of RV-infected primary bronchial epithelial cells activates ILC2s in an IL-33-dependent manner.…”

Section: Viral Infections and Exacerbationsmentioning

confidence: 99%

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

Krohn

Shikhagaie

Golebski

et al. 2017

Allergy

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Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33

Cited by 149 publications

References 53 publications

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

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