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PANETH CELL α-DEFENSINS IN MOUSE ENTERIC INNATE IMMUNITY
by
Jennifer Rose Mastroianni
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR, AND CELLULAR BIOLOGY)
May 2012
Copyright 2012 Jennifer Rose Mastroianni
Object Description
| Title | Paneth cell α-defensins in mouse enteric innate immunity |
| Author | Mastroianni, Jennifer Rose |
| Author email | jmastroi@usc.edu;jennifer.mastroianni@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular and Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-05-05 |
| Date submitted | 2012-05-05 |
| Date approved | 2012-05-06 |
| Restricted until | 2012-11-05 |
| Date published | 2012-11-05 |
| Advisor (committee chair) |
Selsted, Michael E. Ouellette, Andre J. |
| Advisor (committee member) |
Finkel, Steven E. Wong-Beringer, Annie |
| Abstract | α-Defensins are innate immune effector molecules. In mice, the only major site of α-defensin expression is in Paneth cells, a terminally differentiated secretory cell lineage restricted to the small bowel. Mouse enteric α-defensins, termed cryptdins (Crps), are made as inactive precursors and cleaved into biologically active α-defensins by matrix metalloproteinase-7 (MMP7) inside Paneth cells. The peptides are released apically as components of dense core granules at mM concentrations in vivo at the point of secretion, although they are microbicidal at low μM concentrations in vitro. Paneth cell α-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiota. Here functional α-defensins were shown to be abundant in mouse large bowel lumen, demonstrating that α-defensins are highly resistant to proteolysis in vivo and redefining the environment in which Paneth cell α-defensins may mediate innate immunity to include the large bowel. The colonic localization of α-defensins was shown to be independent of the major mucus protein, Muc2, suggesting that intestinal mucus is not required for Paneth cell α-defensins to reach the large bowel. Further, the MMP7-/- mouse was shown to have alternatively processed α-defensins in the large bowel lumen despite absence of the native convertase, MMP7, and the disordered α-defensin proregion was shown to be sensitive to cleavage by other luminal proteases of both host and microbial origin in vitro. Finally, as the large bowel is a site constantly exposed to a high density of anaerobic microorganisms, α-defensin bactericidal activity against anaerobes was investigated. Representative α-defensins were bactericidal against anaerobic bacteria, and α-defensin bactericidal activity against anaerobes and facultative anaerobes was dependent on the oxygen status, test peptide, and target organism species and strain. Taken together, these findings suggest an expanded role for α-defensins in enteric innate immunity, imply that effector molecules may be function at sites far from their point of secretion, and highlight the complexity of the interplay between host defense molecules and microbes. |
| Keyword | antimicrobial peptide; gastrointestinal tract; innate immunity; intestinal microbiota; intestinal mucosa; anaerobe; matrix metalloproteinase; cryptdin; defensin |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Mastroianni, Jennifer Rose |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@dots.usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-Mastroiann-781.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | PANETH CELL α-DEFENSINS IN MOUSE ENTERIC INNATE IMMUNITY by Jennifer Rose Mastroianni A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR, AND CELLULAR BIOLOGY) May 2012 Copyright 2012 Jennifer Rose Mastroianni |
