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 6

HDM-induced immunity to Ascaris parasites is dependent on eosinophils driven by CD4+ T cells.

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HDM-induced immunity to Ascaris parasites is dependent on eosinophils dr...
(A) Experimental design scheme for CD4+ T cell depletion in unsensitized mice followed by Ascaris infection: HDM–Ascaris+ (open circles in B, D, and E) and HDM-sensitized Ascaris-infected (filled circles in B, D, and E) mice received anti-CD4 antibodies before and continuously during the HDM sensitization at days 0, 7, 14, and 21 (group day 0), or after allergic sensitization at days 18 and 25 (group day 18) (n = 6 mice per group). Rat IgG2b antibody was used as the isotype control. (B) Total parasite burden in the BAL at 8 dpi. (C) Representative bright confocal images of the larvae recovered in the BAL at 8 dpi (scale bars: 300 μm). (D) Lung-stage larval development by morphometric analysis of larva size recovered from HDM–Ascaris+ and HDM+Ascaris+ treated with anti-CD4 or isotype control. (E) Characterization of the lung-specific immune response by flow cytometry, showing the frequency of Siglec-F+CD11c– eosinophils and serum HDM-specific IgE and IgG1 antibody levels. Each symbol represents a single mouse, and the horizontal bars are the GMs. P values are indicated in each graph. Nonparametric Kruskal-Wallis test followed by Dunn’s multiple-comparisons test was used for differences among the isotype control–treated groups and anti-CD4–treated groups, and the differences for HDM+Ascaris+ animals treated with IgG2b or anti-CD4 antibodies were considered statistically significant at P < 0.05 by Kruskal-Wallis test followed by Dunn’s multiple-comparisons test.