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6. Regulation of intestinal immunity and tissue repair by enteric glia

Author

Progatzky, Fränze, Shapiro, Michael, Chng, Song Hui, Garcia-Cassani, Bethania, Classon, Cajsa Helena, Sevgi, Selin, Laddach, Anna, Bon-Frauches, Ana Carina, Lasrado, Reena, Rahim, Maryam, Amaniti, Eleni-Maria, Boeing, Stefan, Shah, Kathleen, Entwistle, Lewis J., Suárez-Bonnet, Alejandro, Wilson, Mark S., Stockinger, Brigitta, and Pachnis, Vassilis

Published
2021
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9. Hookworms Evade Host Immunity by Secreting a Deoxyribonuclease to Degrade Neutrophil Extracellular Traps

Author

Bouchery, Tiffany, Moyat, Mati, Sotillo, Javier, Silverstein, Solomon, Volpe, Beatrice, Coakley, Gillian, Tsourouktsoglou, Theodora-Dorita, Becker, Luke, Shah, Kathleen, Kulagin, Manuel, Guiet, Romain, Camberis, Mali, Schmidt, Alfonso, Seitz, Arne, Giacomin, Paul, Le Gros, Graham, Papayannopoulos, Venizelos, Loukas, Alex, and Harris, Nicola L.

Published
2020
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11. Immune serum-activated human macrophages coordinate with eosinophils to immobilize Ascaris suum larvae

Author

Coakley, Gillian, Volpe, Beatrice, Bouchery, Tiffany, Shah, Kathleen, Butler, Alana, Geldhof, Peter, Hatherill, Mark, Horsnell, William G. C., Bieren, Julia Esser-von, Harris, Nicola Laraine, Coakley, Gillian, Volpe, Beatrice, Bouchery, Tiffany, Shah, Kathleen, Butler, Alana, Geldhof, Peter, Hatherill, Mark, Horsnell, William G. C., Bieren, Julia Esser-von, and Harris, Nicola Laraine

Abstract

Helminth infection represents a major health problem causing approximately 5 million disability-adjusted life years worldwide. Concerns that repeated anti-helminthic treatment may lead to drug resistance render it important that vaccines are developed but will require increased understanding of the immune-mediated cellular and antibody responses to helminth infection. IL-4 or antibody-activated murine macrophages are known to immobilize parasitic nematode larvae, but few studies have addressed whether this is translatable to human macrophages. In the current study, we investigated the capacity of human macrophages to recognize and attack larval stages of Ascaris suum, a natural porcine parasite that is genetically similar to the human helminth Ascaris lumbricoides. Human macrophages were able to adhere to and trap A suum larvae in the presence of either human or pig serum containing Ascaris-specific antibodies and other factors. Gene expression analysis of serum-activated macrophages revealed that CCL24, a potent eosinophil attractant, was the most upregulated gene following culture with A suum larvae in vitro, and human eosinophils displayed even greater ability to adhere to, and trap, A suum larvae. These data suggest that immune serum-activated macrophages can recruit eosinophils to the site of infection, where they act in concert to immobilize tissue-migrating Ascaris larvae.

Published
2020
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12. An Exploratory Study On The Functional Significance Of Eosinophil Residency In The Small Intestine Under Homeostatic Conditions

Author

Shah, Kathleen and Harris, Nicola

Subjects
Eosinophils, ECM, Microbiota, Homeostasis, Alarmins, Barrier integrity, Small intestine, Mucosal Immunology, RNA-seq, Imaging
Abstract

The small intestine is a highly dynamic and complex cellular ecosystem, which serves as the primary interface between the host and its environment. A critical component of this ecosystem is the microbiota, which plays a pivotal role in shaping both immune and physiological homeostasis of the host from the moment of birth. However, interaction with the microbiota is a double-edged sword – and the inappropriate establishment of host-microbiota crosstalk could lead to detrimental consequences. Eosinophils are multi-functional granulocytes, recruited into the intestine in early life – but the relevance of this phenomenon has remained enigmatic, given the dogmatic view of these cells as drivers of pathophysiology in type-II immune mediated disorders. Understanding the functional significance of their residency in this tissue under homeostatic conditions warrants further investigation and may provide invaluable insight into their dysregulation in disease. In this thesis, I report our investigation of the contributions of eosinophils to small intestinal homeostasis through a broad characterization of changes in various intestinal functions consequent of eosinophil-deficiency. We approached this expansive question through a combination of histological, cellular and transcriptional analyses, which have afforded us unprecedented insight to eosinophil function in this tissue. Using Δdbl.GATA1 mice, a model of constitutive eosinophil deficiency, we provide evidence for a central role for eosinophils in tissue integrity maintenance in response to the microbiota. We report herein that eosinophil-mediated tissue protection is largely driven by epithelial-derived alarmins, released in response to barrier stress – which equips eosinophils with the capacity to maintain small intestinal integrity and homeostasis through the regulation of extracellular matrix remodelling. In summary, our work provides a functional rationale for the early life recruitment of eosinophils in the small intestine, implicating these cells as key facilitators in the establishment of appropriate host-microbiota crosstalk.

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