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Principal Investigator: Ian Cohn
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $29,474
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The apicomplexan parasite Cryptosporidium is a leading cause of diarrhea and death in immunocompromised
individuals and malnourished children globally. Control of Cryptosporidium requires CD4+ T cells and the
cytokine interferon-γ (IFN-γ), however there are significant gaps in our understanding of the regulation of T cell
responses against the parasite. This is in large part due to difficulties analyzing T cell populations in the gut.
By engineering Cryptosporidium to express MHCII-restricted model antigens, I can identify parasite-specific
CD4+ T cells within the gut. Using this system, I have found that CD4+ T cell responses require type 1
conventional dendritic cells (cDC1s) despite their better-studied role in CD8+ rather than CD4+ T cell
responses. In addition, I have found evidence for a Th17 response elicited by infection, pointing to an IFN-γ-
independent but T cell-dependent mechanism of control of the parasite that has remained elusive. I will utilize
a combination of novel transgenic parasites, genetic mouse models, single-cell RNA sequencing, and high-
dimensional flow cytometry to test which cDC subset(s) are required for CD4+ T cell responses to
Cryptosporidium (SA1), and to investigate the IFN-γ-independent, CD4+ T cell-dependent mechanism(s) of
control with a focus on Th17 responses (SA2). These studies will provide an opportunity to train in cross-
disciplinary approaches in parasitology and immunology to better understand how immunity to infection in the
gut is regulated. The studies proposed here will impact our fundamental understanding of mucosal
immunology and drive treatment and prevention for an important source of childhood mortality.
Terms: <0-11 years old><Address><Antigen Presentation><Antigens><Architecture><Basal Transcription Factor><Basal transcription factor genes><Blocking Antibodies><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Cryptosporidiosis><Cryptosporidium><Cryptosporidium infection><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Death><Defect><Dendritic Cells><Development><Diarrhea><Disease><Disorder><Edodekin Alfa><Engineering><Engineering / Architecture><Epithelial Cells><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-12><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-22><IL12><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune Interferon><Immune system><Immunity><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunology><Immunosuppressed Host><Individual><Infection><Inflammation><Interferon Gamma><Interferon Type II><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-12><Interleukin-17><Intestinal><Intestinal Diseases><Intestinal Disorder><Intestinal parasite><Intestines><Investigation><Knock-out><Knockout><Knowledge><LYT3><Learning><Maintenance><Malnutrition><Measures><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><NKSF><Natural Killer Cell Stimulatory Factor><Nutritional Deficiency><Parasite Control><Parasites><Parasitology><Phenotype><Physicians><Population><Prevention><Production><Regulation><Resistance to infection><Rest><Role><Scientist><Small Intestines><Source><Sterility><Subcellular Process><System><T cell regulation><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Th-1 Cell><Th1 Cells><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Organisms><Type 1 Helper Cell><Undernutrition><Veiled Cells><Work><adaptive immune response><bowel><cytokine><develop a vaccine><develop vaccines><development of a vaccine><developmental><diarrheal disease><diarrheal illness><dietary deficiency><enteral infection><enteric infection><enteric pathogen infection><enteropathogen infection><enteropathogenic infection><flow cytophotometry><genetic approach><genetic strategy><high dimensionality><immune competent><immunogen><immunosuppressed patient><in vivo><infected with Cryptosporidium><infected with enteropathogen><infection resistance><interleukin-22><intestinal epithelium><intestinal infection><intestine disease><intestine disorder><intestine infection><kids><lFN-Gamma><large scale data><large scale data sets><large scale datasets><malnourished><mortality><mouse genetics><mouse model><murine model><novel><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><pathogen><pediatric><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><small bowel><social role><sterile><thymus derived lymphocyte><transcription factor><transgenic><vaccine development><youngster>