Intestinal helminth parasites infect millions of people worldwide and cause significant morbidity. Host- protective type 2 inflammation is characterized by activation of innate immune cells, polarization of nave CD4+ T cells to T helper type 2 cells, anti-helminth epithelial cell responses, and worm expulsion. Recent studies have revealed that basophils, rare innate granulocytes, promote type 2 inflammation and worm expulsion, but the pathways that control basophil effector function following helminth infection remain incompletely defined. However, the Notch signaling pathway stands out as a key candidate that could regulate basophil responses in this context. Ligand binding to a Notch receptor leads to nuclear translocation of the Notch intracellular domain, which can promote transcriptional activation of canonical type 2 inflammation-associated target genes and the development of type 2 inflammatory responses. However, how Notch shapes basophil responses that regulate intestinal type 2 inflammation and helminth expulsion in vivo is unknown. To address this, in preliminary studies, we show for the first time that murine basophils expressed Notch 2 following infection with the intestinal helminth parasite Trichuris muris. Using mice in which Notch signaling is genetically blocked solely in basophils, we demonstrate that while Notch signaling was not required to maintain the basophil population in the steady state, it does contribute to optimal basophil population expansion and helminth clearance following T. muris infection. Finally, we show that Notch signaling regulates cytokine-elicited basophil activation in vitro. Collectively, these data led us to hypothesize that during intestinal helminth parasite infection, basophils upregulate Notch and respond to Notch ligands, mediating optimal basophil population expansion and effector function and efficient helminth expulsion. To test this, we propose three specific aims. Studies in Aim 1 will test how the Notch signaling pathway regulates basophil population expansion and differentiation during type 2 inflammation, employing in vitro assays and in vivo approaches during T. muris infection. Studies in Aim 2 will test how Notch signaling promotes basophil effector function and contributions to type 2 inflammation in vivo using adoptive transfer studies and infection with T. muris, with some studies focusing on the role of Notch 2 in this process. Studies in Aim 3 will test how Notch ligands or helminth proteases could activate Notch signaling in basophils to promote effector function and type 2 inflammation, using in vivo experiments during T. muris infection and in vitro assays. These studies will dissect how Notch signaling regulates basophil responses that drive type 2 inflammation in the intestine following helminth parasite infection. Our results will expand our understanding of intestinal type 2 inflammation and inform the development and use of therapies that target Notch to treat type 2 inflammatory diseases.

Public Health Relevance

Intestinal helminth parasites infect millions worldwide and cause significant morbidity. Our studies will test how Notch signaling in basophils, key innate granulocytes that promote helminth expulsion, regulates host- protective type 2 inflammation during intestinal helminth infection. Our results will increase our understanding of the role of the Notch signaling pathway and basophils in regulating anti-helminth responses and will inform the development of new therapies to treat type 2 inflammation in the intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI132708-01
Application #
9367027
Study Section
Immunity and Host Defense (IHD)
Program Officer
Rothermel, Annette L
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cornell University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Oyesola, Oyebola O; Früh, Simon P; Webb, Lauren M et al. (2018) Cytokines and beyond: Regulation of innate immune responses during helminth infection. Cytokine :
Webb, Lauren M; Tait Wojno, Elia D (2017) The role of rare innate immune cells in Type 2 immune activation against parasitic helminths. Parasitology 144:1288-1301