Hypothesis: Leptin is an important regulator of the intestinal inflammatory response to infection, and does so through its effects on either hematopoietic or non-hematopoietic cells of the gut. Leptin and leptin receptor are expressed in the intestinal epithelium and in infiltrating mononuclear cells in the lamina propria. Leptin controls expression of epithelial sodium/glucose and peptide transporters, regulates apoptosis, and induces intestinal inflammation via T lymphocytes. We and others have observed that mice deficient in leptin (ob/ob) or functional leptin receptor (db/db) have altered susceptibility to amebiasis and Clostridium difficile, as well as experimentally-induced inflammatory bowel disease. These results suggest that leptin may have broad regulatory roles in enteric infection and inflammation. Intriguingly, a common (present in one half of the CephUtah population analyzed by HapMap) single amino acid polymorphismm in the leptin receptor (that alters its affinity for leptin) is associated with resistance in children to amebiasis, and in adults to amebic liver abscess. We propose to study the mechanisms by which leptin and its receptor regulate intestinal defense against infection in mice and in humans. First we will test how general the observation is of the link of leptin to intestinal infection and inflammation. With collaborating investigators within MARGE we will determine if ob/ob (leptin deficient) and db/db (leptin receptor deficient) mice have increased susceptibility to infection and inflammation due to Giardia lamblia, Cryptospordium pan/urn, enteroaggregative E. coli and C. difficile. We will then determine the contribution to infection and inflammation of leptin and leptin receptor in intestinal epithelium vs. bone marrow-derived cells for a single infectious agent, and its dependency upon STATS signaling. Finally we will extend these observations to humans by testing for associations of protection from Giardia lamblia and enteroaggregative E. coli with the leptin receptor polymorphism found to be protective from amebiasis.

Public Health Relevance

Successful completion of these studies will provide (1) an understanding of the role of leptin in the intestinal response to infection;(2) a mechanistic understanding of how leptin acts in the gut;and (3) the extent to which common genetic polymorphisms in the leptin signaling pathway sensitize humans to enteric infection. Novel management of enteric infection and inflammation via modulation of leptin is a promise of this work.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-10
Application #
8442358
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$270,087
Indirect Cost
$32,791
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Freedman, John C; Theoret, James R; Wisniewski, Jessica A et al. (2015) Clostridium perfringens type A-E toxin plasmids. Res Microbiol 166:264-79
Li, Jihong; McClane, Bruce A (2014) Contributions of NanI sialidase to Caco-2 cell adherence by Clostridium perfringens type A and C strains causing human intestinal disease. Infect Immun 82:4620-30
Moy, Ryan H; Gold, Beth; Molleston, Jerome M et al. (2014) Antiviral autophagy restrictsRift Valley fever virus infection and is conserved from flies to mammals. Immunity 40:51-65
Cuevas, Christian D; Ross, Susan R (2014) Toll-like receptor 2-mediated innate immune responses against Junín virus in mice lead to antiviral adaptive immune responses during systemic infection and do not affect viral replication in the brain. J Virol 88:7703-14
Boyd, Mary Adetinuke; Tennant, Sharon M; Saague, Venant A et al. (2014) Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines. Clin Vaccine Immunol 21:712-21
Su, Yi-Hsuan; Tsegaye, Mikiyas; Varhue, Walter et al. (2014) Quantitative dielectrophoretic tracking for characterization and separation of persistent subpopulations of Cryptosporidium parvum. Analyst 139:66-73
Xu, Jie; Cherry, Sara (2014) Viruses and antiviral immunity in Drosophila. Dev Comp Immunol 42:67-84
Uzal, Francisco A; Freedman, John C; Shrestha, Archana et al. (2014) Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease. Future Microbiol 9:361-77
Weir, Dawn L; Laing, Eric D; Smith, Ina L et al. (2014) Host cell virus entry mediated by Australian bat lyssavirus G envelope glycoprotein occurs through a clathrin-mediated endocytic pathway that requires actin and Rab5. Virol J 11:40
Weir, Dawn L; Annand, Edward J; Reid, Peter A et al. (2014) Recent observations on Australian bat lyssavirus tropism and viral entry. Viruses 6:909-26

Showing the most recent 10 out of 299 publications