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 #
5U54AI057168-09
Application #
8375132
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$312,200
Indirect Cost
$42,042
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kaempfer, Raymond; Popugailo, Andrey; Levy, Revital et al. (2017) Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint. Receptors Clin Investig 4:
Bridge, Dacie R; Blum, Faith C; Jang, Sungil et al. (2017) Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways. Sci Rep 7:11057
Molleston, Jerome M; Cherry, Sara (2017) Attacked from All Sides: RNA Decay in Antiviral Defense. Viruses 9:
Cifuentes-Muñoz, Nicolás; Sun, Weina; Ray, Greeshma et al. (2017) Mutations in the Transmembrane Domain and Cytoplasmic Tail of Hendra Virus Fusion Protein Disrupt Virus-Like-Particle Assembly. J Virol 91:
Wahid, Rezwanul; Fresnay, Stephanie; Levine, Myron M et al. (2016) Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol 173:87-95
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Ramachandran, Girish; Tennant, Sharon M; Boyd, Mary A et al. (2016) Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella. PLoS One 11:e0151875
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Riblett, Amber M; Blomen, Vincent A; Jae, Lucas T et al. (2016) A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. J Virol 90:1414-23
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510

Showing the most recent 10 out of 373 publications