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 5

Ascaris larval migration and development occur normally in allergic eosinophil-deficient mice.

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Ascaris larval migration and development occur normally in allergic eos...
(A) Experimental design scheme for HDM allergic sensitization followed by Ascaris infection in WT BALB/c and eosinophil-knockout mice (ΔdblGATA). (B–D) Total parasite burden in the lungs and BAL at day 8 of infection (n = 17 mice per group) (B), as well as a representative bright confocal image of lung-stage larvae recovered from Ascaris-infected ΔdblGATA mice following or not following HDM allergic sensitization (HDM–Ascaris+ vs. HDM+Ascaris+) (scale bars: 200 μm) (C) and a morphometric analysis of these larvae recovered (D). Three independent experiments were performed. (E–I) Characterization of the lung-specific immune response of HDM+Ascaris+ WT (n = 5 mice) (dark green triangles) and HDM+Ascaris+ ΔdblGATA mice (n = 5 mice) (light green triangles) by flow cytometry phenotypic analysis, cytokine production, M2 macrophage marker gene expression, and histology of lung epithelium. (E) Eosinophils. (F) IL-4, IL-13, and IL-33 cytokine quantification. (G) IL-5– or IL-13–producing CD4+ Th2 cell frequency (n = 7 mice per group). (H) Arginase-1 and Fizz-1 gene expression in the lungs. (I) Lung sections stained by AB/PAS showing mucus production by the goblet cells in the lung epithelium (in blue; arrows) (original magnification, ×16). Each symbol represents a single mouse, and the horizontal bars are the GMs. P values are indicated in each graph. Differences between HDM+Ascaris+ (WT) and HDM+Ascaris+ (GATA) mice were considered statistically significant at P < 0.05 by unpaired Mann-Whitney test. *Significantly different (P < 0.05) from naive (HDM–Ascaris–) group. Kruskal-Wallis test followed by Dunn’s multiple-comparisons test was used to compare WT HDM+Ascaris+ versus ΔdblGATA HDM+Ascaris+ in B and D.