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Principal Investigator: Reinhard Hinterleitner
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $66,992
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Enteric helminth infections remain a significant global health problem. Although infections by these parasites are
generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anemia
and malnourishment. Infections are strongly associated with protective type-2 immune mediated intestinal
inflammation, observed across species, including mice and humans, and characterized by innate lymphoid cell
(ILC2), T helper 2 (Th2), and eosinophil recruitment and tissue injury. Mouse models of infection with intestinal
parasites have been established to study the cellular and molecular mechanisms of type-2 immune responses
in greater detail: Helminths, such as Nippostrongylus brasiliensis and Heligmosomoides polygyrus, and certain
protists of the order Trichomonadida induce acute host type-2 immune defense responses in the small intestine
upon infection. Type-2 immune responses are initiated by parasite sensing interleukin-25 (IL-25) producing
epithelial tuft cells, resulting in the activation of IL-13 producing ILC2 that in turn signal back on epithelial cells.
This feedforward IL-25-ILC2-IL-13 circuit amplifies type-2 immune responses and initiates massive tissue
remodeling including tuft- and goblet cell hyperplasia, and mucus production resulting in the containment of
intestinal parasites.
Despite the previous advancements in our understanding in immune-tissue crosstalk in type-2 mediated
inflammation, we lack a complete understanding of the detailed processes underlying parasite-induced type-2
immune responses in epithelial cells. This limits effective treatment options to enteric parasitic infections. The
goal of this proposal is therefore to generate new tools to study epithelial-cell intrinsic regulation of type-2 immune
responses. In aim 1, we will generate an epithelial-cell specific conditional knock-out mouse model using
CRISPR/Cas9. In aim 2, we will validate the new mouse model in Nippostrongylus brasiliensis and
Heligmosomoides polygyrus helminth infection models. These findings may provide rational approaches to
modulate type-2 inflammation to enteric parasite infections in humans.
Terms: <Acute><Address><Alleles><Allelomorphs><Anemia><Antigen Presentation><Antigen-Presenting Cells><Award><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Back><Binding><Blood Eosinophil><Body Tissues><C-terminal><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Caspase><Caspase Gene><Cathepsins><Cell Body><Cell Communication and Signaling><Cell Death><Cell Membrane Lipids><Cell Signaling><Cell-Death Protease><Cells><Class II Antigens><Class II Major Histocompatibility Antigens><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Containment><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Data><Dendritic Cells><Disease><Disorder><Dorsum><Enteral><Enteric><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Epithelial Cells><Epithelium><Esteroproteases><Frequencies><Future><Gene Cluster><Genetics-Mutagenesis><Goals><Goblet Cells><Gut Epithelium><Heligmosomoides polygyrus><Helminths><Histocompatibility Antigens Class II><Human><Hyperplasia><Hyperplastic><I-A Antigen><ICE-like protease><IL-13><IL13><Ia Antigens><Ia-Like Antigens><Immune><Immune Response Antigens><Immune response><Immune-Response-Associated Antigens><Immunes><Immunity><Immunological response><Impairment><Infection><Inflammation><Interleukin-13><Interleukins><Intestinal><Intestinal parasite><Intestines><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Laboratories><LoxP-flanked allele><Lymphoid Cell><MHC Class II Molecule><MHC Class II Protein><MHC class II antigen><Macrophage><Major Histocompatibility Complex Class II><Malnutrition><Marrow Eosinophil><Mediating><Membrane Lipids><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mouse Strains><Mucosa><Mucosal Tissue><Mucous Membrane><Mucous body substance><Mucus><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Mφ><N-terminal><NH2-terminal><Nematospiroides dubius><Nippostrongylus><Null Mouse><Nutritional Deficiency><Organoids><Parasites><Parasitic Worms><Parasitic infection><Peptidases><Peptide Hydrolases><Process><Production><Protease Gene><Proteases><Protein Cleavage><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><Regulation><Reporting><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Small Intestines><Study models><T-Cells><T-Lymphocyte><Tamoxifen><Testing><Tissues><Trichomonadida><Undernutrition><Veiled Cells><accessory cell><biological signal transduction><bowel><bowel inflammation><chronic infection><conditional knock-out><conditional knockout><cystein protease><cystein proteinase><cysteine endopeptidase><cytokine><defense response><dietary deficiency><effective therapy><effective treatment><enteral infection><enteric infection><enteric pathogen infection><enteropathogen infection><enteropathogenic infection><eosinophil><experiment><experimental research><experimental study><experiments><floxed><floxed allele><gastrointestinal><gastrointestinal epithelium><global health><gut inflammation><helminth infection><helminthic infection><host response><immune system response><immunoresponse><infected with enteropathogen><infected with helminth><inflamed bowel><inflamed gut><inflamed intestine><inhibitor><injury to tissue><intestinal epithelium><intestinal infection><intestinal inflammation><intestine infection><malnourished><mesenteric lymph node><mesentery lymph node><mouse model><mucous><murine model><necrocytosis><novel><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><parasite infection><persistent infection><physiological defense response><protein expression><recruit><response><small bowel><social role><thymus derived lymphocyte><tissue injury><tool>