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 4

Ascaris infection in preallergic animals is associated with an eosinophil-, M2 macrophage–, and mucus-rich environment in the lungs.

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Ascaris infection in preallergic animals is associated with an eosinoph...
(A) Representative flow cytometry dot plots of the lungs showing the frequencies of Siglec-F+CD11c– eosinophils at day 8. (B and C) Absolute number of eosinophils at different time points (B), and eosinophil activation assay by quantification of eosinophil peroxidase (EPO) levels (C). (D) Representative flow cytometry dot plot of the lungs showing the frequencies of CD11b+F4/80+ macrophages at day 8. (E) Absolute number of macrophages 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). (F) Heatmap analysis to compare gene expression of arginase-1 (Arg-1) and iNOS in the lungs of mice from all groups at day 5 (n = 9 mice per group) and day 8 (n = 10 mice per group). In the heatmap, each row represents the expression level of Arg-1 and iNOS per animal, and the columns represent the different groups. Pink represents highly expressed; yellow means low expression value. Each symbol represents a single mouse, and the horizontal bars are the GMs. 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. Wilcoxon matched-pairs test was used for the gene expression analysis between HDM+Ascaris– mice and HDM+Ascaris+ mice.