Members of the immunoglobulin gene superfamily (IgSF) mediate innate and adaptive immunity in jawed vertebrates. Diversity of the IgSF-innate immune receptors is maintained in the germline, whereas adaptive receptors derive unique recognition function through somatic rearrangement and other modifications of immune genes in individual cells. The evolutionary origins of the rearranging IgSF receptors that mediate adaptive immunity is hypothesized to have occurred after the divergence of jawless and jawed vertebrate forms. However, the nature of the innate receptor from which the ancestral adaptive immune receptor derived is not understood, nor are the origins and patterns of divergence of the complex IgSF families, such as the activating/inhibitory leukocyte regulatory receptors, that mediate different innate immune functions. Major voids in understanding immune receptor diversification will be filled by characterizing the structure and function of IgSF genes in species representing critical early branch points in chordate evolution, including: 1) a highly diversified family of activating/inhibitory IgSF receptors in cartilaginous fish, 2) several immune-type IgSF genes in a jawless vertebrate, and 3) a multigene family encoding diversified IgSF related variable regions in a protochordate. The genetic basis for receptor diversity will be defined, the cell lineages expressing the receptors will be identified and potential receptor-ligand interactions will be characterized. Although the questions posed by each of the model systems require different approaches for gene discovery and characterization, several novel technologies are common to the various projects, including: 1) a highly efficient cloning method that requires knowledge of only a single short peptide motif, 2) unique soluble chimeric receptor constructs, and 3) a sensitive GFP-coupled reporter assay. In addition, methods used in studies of natural killer function and pathogen isolation will be adapted to these investigations. This broad-based approach will define the fundamental mechanisms that underlie the evolutionary divergence of the IgSF immune effectors and identify heretofore, unrecognized genetic and functional relationships between adaptive and innate immunity. Such information is fundamental to understanding the basis for self-nonself discrimination and how structural diversification relates to immune specificity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023338-21
Application #
6890367
Study Section
Special Emphasis Panel (ZRG1-IMB (03))
Program Officer
Kirkham, Perry M
Project Start
1985-09-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
21
Fiscal Year
2005
Total Cost
$362,500
Indirect Cost
Name
University of South Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Liberti, Assunta; Zucchetti, Ivana; Melillo, Daniela et al. (2018) Chitin protects the gut epithelial barrier in a protochordate model of DSS-induced colitis. Biol Open 7:
Zhang, Linlin; Li, Li; Guo, Ximing et al. (2015) Massive expansion and functional divergence of innate immune genes in a protostome. Sci Rep 5:8693
Liberti, Assunta; Leigh, Brittany; De Santis, Rosaria et al. (2015) An Immune Effector System in the Protochordate Gut Sheds Light on Fundamental Aspects of Vertebrate Immunity. Results Probl Cell Differ 57:159-73
Dishaw, Larry J; Flores-Torres, Jaime; Lax, Simon et al. (2014) The gut of geographically disparate Ciona intestinalis harbors a core microbiota. PLoS One 9:e93386
Saha, Nil Ratan; Ota, Tatsuya; Litman, Gary W et al. (2014) Genome complexity in the coelacanth is reflected in its adaptive immune system. J Exp Zool B Mol Dev Evol 322:438-63
Rodríguez-Nunez, Iván; Wcisel, Dustin J; Litman, Gary W et al. (2014) Multigene families of immunoglobulin domain-containing innate immune receptors in zebrafish: deciphering the differences. Dev Comp Immunol 46:24-34
Dishaw, Larry J; Cannon, John P; Litman, Gary W et al. (2014) Immune-directed support of rich microbial communities in the gut has ancient roots. Dev Comp Immunol 47:36-51
Liberti, Assunta; Melillo, Daniela; Zucchetti, Ivana et al. (2014) Expression of Ciona intestinalis variable region-containing chitin-binding proteins during development of the gastrointestinal tract and their role in host-microbe interactions. PLoS One 9:e94984
Kortum, Amanda N; Rodriguez-Nunez, Ivan; Yang, Jibing et al. (2014) Differential expression and ligand binding indicate alternative functions for zebrafish polymeric immunoglobulin receptor (pIgR) and a family of pIgR-like (PIGRL) proteins. Immunogenetics 66:267-79
Cannon, John P; O'Driscoll, Marci; Litman, Gary W (2012) Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 64:39-47

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