Respiratory Syncytial Virus Infection Activates IL-13-Producing Group 2 Innate Lymphoid Cells via Thymic Stromal Lymphopoietin

Publication date: Available online 9 April 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Matthew T. Stier, Melissa H. Bloodworth, Shinji Toki, Dawn C. Newcomb, Kasia Goleniewska, Kelli L. Boyd, Marc Quitalig, Anne L. Hotard, Martin L. Moore, Tina V. Hartert, Baohua Zhou, Andrew N. McKenzie, R. Stokes Peebles
BackgroundRespiratory syncytial virus (RSV) is a major healthcare burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated illness is in part caused by immunopathology associated with a robust type 2 response.ObjectiveTo determine the capacity of RSV-infection to stimulate group 2 innate lymphoid cells (ILC2) and the associated mechanism in a murine model.MethodsWT BALB/c, TSLPR KO, or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4-6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with two additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential.ResultsRSV induced a 3-fold increase in the number of IL-13-producing ILC2 at day 4 post-infection with a concurrent increase in total lung IL-13 levels. Both TSLP and IL-33 were increased 12 hours post-infection. TSLPR KO mice failed to mount an IL-13-producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13-producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13-producing ILC2 via a TSLP-dependent mechanism.ConclusionThese data demonstrate that multiple pathogenic strains of RSV induce IL-13-producing ILC2 proliferation and activation via a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection.

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Teaser

In a murine model, RSV induced activation of ILC2 that produced IL-13, a Th2 cytokine that mediates airway obstruction and has been linked to severe RSV illness. This ILC2 activation was dependent upon TSLP, an emerging therapeutic target for Th2-driven illness.


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