title: Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin.
abstract: Respiratory syncytial virus (RSV) is a major health care 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.
  
  
  
  We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model.
  
  
  
  Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 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 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential.
  
  
  
  RSV induced a 3-fold increase in the number of IL-13-producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not 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 levels, 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 ILC2s through a TSLP-dependent mechanism.
  
  
  
  These data demonstrate that multiple pathogenic strains of RSV induce IL-13-producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Stier
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Bloodworth
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Shinji
authors.initials: S
authors.lastname: Toki
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn; Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Marc
authors.initials: M
authors.lastname: Quitalig
authors.affiliation: Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, Ga.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Hotard
authors.affiliation: Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, Ga.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Moore
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Tina V
authors.initials: TV
authors.lastname: Hartert
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Baohua
authors.initials: B
authors.lastname: Zhou
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge University, Cambridge, United Kingdom.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tenn; Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn. Electronic address: stokes.peebles@vanderbilt.edu.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D018793:Interleukin-13 / Q000276:immunology*; D000067596:Interleukin-33 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008214:Lymphocytes / Q000276:immunology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D019562:Viral Load; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: Group 2 innate lymphoid cells; IL-13; IL-33; respiratory syncytial virus; thymic stromal lymphopoietin; type 2 immunity (T(H)2)