Allergen presensitization drives an eosinophil-dependent arrest in lung-specific helminth development
Pedro H. Gazzinelli-Guimaraes, … , Ricardo T. Fujiwara, Thomas B. Nutman
Pedro H. Gazzinelli-Guimaraes, … , Ricardo T. Fujiwara, Thomas B. Nutman
Published August 5, 2019
Citation Information: J Clin Invest. 2019;129(9):3686-3701. https://doi.org/10.1172/JCI127963.
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Research Article Immunology Infectious disease

Allergen presensitization drives an eosinophil-dependent arrest in lung-specific helminth development

Abstract

This study investigates the relationship between helminth infection and allergic sensitization by assessing the influence of preexisting allergy on the outcome of helminth infections, rather than the more traditional approach in which the helminth infection precedes the onset of allergy. Here we used a murine model of house dust mite–induced (HDM-induced) allergic inflammation followed by Ascaris infection to demonstrate that allergic sensitization drives an eosinophil-rich pulmonary type 2 immune response (Th2 cells, M2 macrophages, type 2 innate lymphoid cells, IL-33, IL-4, IL-13, and mucus) that directly hinders larval development and reduces markedly the parasite burden in the lungs. This effect is dependent on the presence of eosinophils, as eosinophil-deficient mice were unable to limit parasite development or numbers. In vivo administration of neutralizing antibodies against CD4 prior to HDM sensitization significantly reduced eosinophils in the lungs, resulting in the reversal of the HDM-induced Ascaris larval killing. Our data suggest that HDM allergic sensitization drives a response that mimics a primary Ascaris infection, such that CD4+ Th2-mediated eosinophil-dependent helminth larval killing in the lung tissue occurs. This study provides insight into the mechanisms underlying tissue-specific responses that drive a protective response against the early stages of the helminths prior to their establishing long-lasting infections in the host.

Authors

Pedro H. Gazzinelli-Guimaraes, Rafael de Queiroz Prado, Alessandra Ricciardi, Sandra Bonne-Année, Joshua Sciurba, Erik P. Karmele, Ricardo T. Fujiwara, Thomas B. Nutman

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Figure 3

HDM sensitization followed by Ascaris infection drives a strong innate and adaptive type 2 immunity in the lungs.

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HDM sensitization followed by Ascaris infection drives a strong innate a...
(A) Representative flow cytometry dot plot of lung homogenates, gated on Lin–CD45+TCR-β+CD4+ T cells, showing the frequencies of IL-5 and IL-13 (top) and IFN-γ and IL-17 (bottom) in the different groups at day 8. (B–D) The net frequency of IL-5+ or IL-13+ CD4+ Th2 cells (B), IFN-γ+ CD4+ Th1 cells (C), and IL-17A+ CD4+ Th17 cells (D) was assessed at different time points: day 5 (n = 9 mice per group), day 8 (n = 10 mice per group), and day 18 (n = 10 mice per group). Boolean analysis was performed to exclude multifunctional CD4+ T cells expressing IL-5, IL-13, IFN-γ, and IL-17 simultaneously. (E) Frequency of total innate lymphoid cells (ILCs) gated as CD45+Lin–CD4–TCR-β–Thy.1.2+ in the different groups at day 8 of infection, as well as the proportion of ILC1s, ILC2s, and ILC3s, based on the expression of the signature cytokines IFN-γ, IL-5/IL-13, and IL-17A, respectively, after PMA/ionomycin stimulation. Each symbol represents a single mouse, and the horizontal bars are the GMs. Net frequency of CD4+ T cells was calculated by subtraction of the baseline frequency (nonstimulated) from the frequency following stimulation with PMA/ionomycin. P values are indicated in each graph. Differences were considered statistically significant at P < 0.05 by Kruskal-Wallis test followed by Dunn’s multiple-comparisons test, used for all comparisons; *significantly different (P < 0.05) from naive (HDM–Ascaris–) group.