Date Published: October 16, 2015
Publisher: Public Library of Science
Author(s): Jordy Saravia, Dahui You, Bishwas Shrestha, Sridhar Jaligama, David Siefker, Greg I. Lee, Jeffrey N. Harding, Tamekia L. Jones, Cynthia Rovnaghi, Bindiya Bagga, John P. DeVincenzo, Stephania A. Cormier, Paul G. Thomas.
Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants [1, 2], and is globally responsible for an estimated 64 million cases and 160,000 deaths each year . In infants, severe RSV infection is characterized by bronchiolitis, interstitial pneumonitis, alveolitis , and a T helper 2 (Th2)-biased immune response in the lungs (i.e., Th2 cells, eosinophilia, mucus). One important correlate of severe RSV infection is age; most severe disease occurs in children <1 yr of age , with highest hospitalization rates occurring in those <6 months of age . More recently, our understanding of RSV has been aided by the use of an age-appropriate mouse model in which neonatal mice infected with RSV exhibit an immunological (Th2 biased) and pathophysiological (pulmonary inflammation, eosinophilia, mucus hyperproduction, and long-term airways dysfunction) phenotype typically seen in human infants with severe RSV [6, 7]. Infant susceptibility to severe RSV infection remains a significant global health burden for which no protective vaccine or adequate therapeutic is yet available. In recent years, it has become increasingly clear that age-dependent inherent differences in immunity play a vital role in both the magnitude [17, 18] and type  of responses to RSV. Interestingly, while infants are capable of mounting robust type-1 responses to other respiratory viruses such as influenza , they uniquely favor type-2 responses and the development of Th2 adaptive immunity (i.e. elevated IL-13 compared to IFN-γ) to RSV. Age at initial infection is critical in determining initial and subsequent immune responses to RSV  and in predicting subsequent wheeze/asthma [6, 7, 21, 22]. The role of age in dictating the response to RSV remains incompletely understood with respect to mechanism. Source: http://doi.org/10.1371/journal.ppat.1005217