Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin

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

Research output: Contribution to journalArticle

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Abstract

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Apr 23 2015

Fingerprint

Respiratory Syncytial Virus Infections
Interleukin-13
Respiratory Syncytial Viruses
Lymphocytes
Mucus
Viral Load
Knockout Mice
Lung
Infection
thymic stromal lymphopoietin
Viral Proteins
Neutralizing Antibodies
Weight Loss
Morbidity
Delivery of Health Care
Mortality

Keywords

  • Group 2 innate lymphoid cells
  • IL-13
  • IL-33
  • Respiratory syncytial virus
  • Thymic stromal lymphopoietin
  • Type 2 immunity (T2)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. / Stier, Matthew T.; Bloodworth, Melissa H.; Toki, Shinji; Newcomb, Dawn C.; Goleniewska, Kasia; Boyd, Kelli L.; Quitalig, Marc; Hotard, Anne L.; Moore, Martin L.; Hartert, Tina V.; Zhou, Baohua; McKenzie, Andrew N.; Peebles, R. Stokes.

In: Journal of Allergy and Clinical Immunology, 23.04.2015.

Research output: Contribution to journalArticle

Stier, MT, Bloodworth, MH, Toki, S, Newcomb, DC, Goleniewska, K, Boyd, KL, Quitalig, M, Hotard, AL, Moore, ML, Hartert, TV, Zhou, B, McKenzie, AN & Peebles, RS 2015, 'Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.01.050
Stier, Matthew T. ; Bloodworth, Melissa H. ; Toki, Shinji ; Newcomb, Dawn C. ; Goleniewska, Kasia ; Boyd, Kelli L. ; Quitalig, Marc ; Hotard, Anne L. ; Moore, Martin L. ; Hartert, Tina V. ; Zhou, Baohua ; McKenzie, Andrew N. ; Peebles, R. Stokes. / Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. In: Journal of Allergy and Clinical Immunology. 2015.
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AU - Bloodworth, Melissa H.

AU - Toki, Shinji

AU - Newcomb, Dawn C.

AU - Goleniewska, Kasia

AU - Boyd, Kelli L.

AU - Quitalig, Marc

AU - Hotard, Anne L.

AU - Moore, Martin L.

AU - Hartert, Tina V.

AU - Zhou, Baohua

AU - McKenzie, Andrew N.

AU - Peebles, R. Stokes

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N2 - Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

AB - Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

KW - Group 2 innate lymphoid cells

KW - IL-13

KW - IL-33

KW - Respiratory syncytial virus

KW - Thymic stromal lymphopoietin

KW - Type 2 immunity (T2)

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